The Curious Wavefunction

Stimulating quasi-erotic excitement through organic structure determination

noreply@blogger.com (Wavefunction) — Thu, 02 Sep 2010 17:57:00 +0000

Thanks to the graces of the intertubes I came across this rare and fascinating video of R B Woodward put up by some kind soul a couple of months ago. The novelty of the quintessential Bostonian accent, the cigarette and glass of scotch adorning the lectern and the man in blue are only eclipsed by his achievements and what he has to say. He especially saves the coup de grace for the end.

Woodward essentially sheds light on the remarkable developments in organic chemistry until then by providing contrasting examples from his own research. He emphasizes how times had changed between his own work and the state of the art in 1979. One can make similar comparisons right now. Woodward basically attributes the astonishing progress in organic chemistry in the last forty years to two factors- an intense infusion of theoretical concepts in their most general form (MO theory, quantum chemistry etc.), and the path-breaking developments in physical methods, including IR, UV and NMR spectroscopy and x-ray crystallography. He then provides famous examples from his own work to starkly emphasize the contrast.

The first example is from his synthesis of quinine. In this synthesis, one of the steps involved the elimination of a quaternary ammonium ion to form a double bond. The question was whether the double bond formed was a vinyl double bond or an ethylidene double bond; it was the vinyl that was desired. Nowadays, and even in 1979, a graduate student could settle this question in literally a matter of minutes, but at that point (circa 1945), Harvard did not even have the experimental facilities necessary to chemically investigate this fact. Woodward had to send the sample to the famous chemist Max Tischler at Merck. Tischler got back saying it was an ethylidene. This threw the chemists into a state of despondency for a few days, until Tischler called back to inform them that Merck had made a mistake and it was in fact the vinyl double bond. The tense drama during this situation seems almost comical in the light of modern structure determination methods.

The second example concerned Woodward’s astonishing decade-long synthesis of Vitamin B12. He expressed wonder how an NMR spectrometer had been able to obtain the natural abundance C13 spectrum of 1 mg of the synthetic finished product using 995,000 transient scans. This incredulity would sound almost laughable today. Capillary NMR and 1 GHZ machines have pushed the science and art of structure determination to limits, and doing a million scans on 1 mg of material is almost old hat.

The third example was a nice little anecdote. Woodward had a wager with Linus Pauling in the 1950s whether he could chemically determine the structure of the antibiotic terramycin faster than Pauling could do it with x-ray crystallography. Woodward won the wager, but also admitted that he would probably lose it today because x-ray crystallography had gotten so powerful. Today x-ray crystallography is already at the top of its game, and who knows what breakthroughs in structure determination would be possible with AFM and STM.

The last example cracked everyone up. Woodward talked about the structure determination of cantharidin, the active principle of the Spanish fly. Chemists had isolated up to 500 grams of cantharidin to find out its structure. “Just think of it, 500 grams of cantharidin”, says Woodward. “There are many people who would think it’s an absolute tragedy. Realize that that would be enough to keep the entire population of Spain in a state of quasi-erotic excitement for a period of a full year!”

What would be Woodward’s reaction if he were to suddenly materialize today in a poof of chemical pixie dust and survey the synthesis landscape? My humble guess is that he would not be too impressed. He would undoubtedly be excited by the development of the Sharpless and Grubbs methods and the great success of the palladium-catalyzed reactions (not to mention the general development of organometallic chemistry, in the founding of which he himself played a role). But beyond that, I doubt if he would notice any fundamental change in the science of organic synthesis compared to what he witnessed and orchestrated during his own lifetime. Sure, things have become more efficient, streamlined and automated, but those details, as impressive as they are, are really operational details.

My personal guess is that Woodward would be much more impressed by the application of organic synthesis to biology and materials science. But as for the science itself, it probably still stands very close to where Woodward left it thirty years ago, and the whiz-kid from Quincy would have little trouble bringing himself up to speed on it in no time at all.

Assessing computationally designed enzymes

noreply@blogger.com (Wavefunction) — Mon, 30 Aug 2010 21:38:00 +0000

One of the most promising recent developments in computational biochemistry is the development of potential capability to computationally design entirely new enzymes from scratch that can perform reactions inaccessible to naturally occurring proteins. Such enzymes can be of great utility as novel biofuels, synthetic reagents and new drugs. A particularly noteworthy set of publications in this regard was from David Baker’s and Ken Houk’s groups in Seattle and Los Angeles. In 2008, the groups designed an enzyme for performing a base-catalyzed Kemp elimination, a reaction which converts a benzisoxazole into a cyanophenoxide by proton abstraction.

A couple of months back, they again made news by designing a Diels-Alderase from scratch, an enzyme catalyzing the DA reaction whose natural counterpart does not exist. Although the catalytic rates they obtained were relatively modest compared to the best rates seen in nature, this is still an important and remarkable step forward.

The studies hinged on two tools- quantum mechanical design of a transition state for the enzymatic reaction, and buildup of the protein architecture around this ideal transition state using the program Rosetta. In the first step, a transition state for the reaction was surrounded by specific amino acid residues and optimized in an ideal geometry. This arrangement is called a “theozyme”, an ideal, minimal theoretical construct. In the second step, Rosetta was used to ‘embed’ this theozyme in a protein framework borrowed from existing protein structures in the PDB. Iterative cycles of optimization of the amino acids around the reactants led to several designs. Some of these designs turned out to be active, and crystal structures revealed the remarkable similarity between the computer and real-life counterparts. However, there was no easy way except actual testing to distinguish active and inactive designs beforehand (the inactive designs could not be crystallized since by definition they were probably too unstable to form crystals).

Now a new analysis nicely looks at the difference between the active and inactive designs obtained for the Kemp elimination. The authors first try to use static quantum chemistry calculations to resolve the difference between the two sets. Unfortunately this does not work very well since the energy difference between the sets are quite small, about 2 kcal/mol, and QM methods for such complex systems can often produce comparable errors.

However, enzymes are dynamic creatures, and it’s probably not too surprising that one has to resort to dynamical studies to discern the differences between active and inactive structures. To this end, the authors used 20 ns MD simulations. They compared the results with two designed Kemp eliminators (including one antibody) whose crystal structures are available. Firstly, they simply observed the mobility of the residues in the active sites and found out that in general, residues in the active designs don’t move around as much as those in the inactive ones, indicating stable packing. Then they looked at the hydrogen bonds holding the reactants together. In general, they found a tighter distribution of hydrogen bond angles in the active and crystallized structures compared to the inactive ones. This observation would be in keeping in line with the optimized hydrogen bonding networks in active sites. Lastly, they looked at accessibility of water in the active site. The base involved in the Kemp elimination is a carboxylate. Ideally, this carboxylate would not be solvated so that it is free to serve as a base. Indeed, analysis of water molecules surrounding this carboxylate indicated that while the carboxylates in the active, crystallized proteins are almost completely free of water molecules, the carboxylates in the inactive designs are typically surrounded by a couple of water molecules. This also again confirms the ‘looser’ packing in the inactive sites.

This is a nice study because it not only validates MD as a possible tool to distinguish and rank active and inactive designed enzymes, but it also provides insights into the basic physical features of optimized enzyme active sites. Compact packed side-chains, optimal hydrogen bonding geometries and relative inaccessibility of key residues to water is about what you would expect evolution to do when asked to come up with good enzyme designs.

Kiss, G., Röthlisberger, D., Baker, D., & Houk, K. (2010). Evaluation and ranking of enzyme designs Protein Science DOI: 10.1002/pro.462

Riding off into the twilight...

noreply@blogger.com (Wavefunction) — Mon, 30 Aug 2010 12:13:00 +0000

In "The Twilight of the Bombs", the last volume of his breathtaking account of nuclear history, Richard Rhodes describes the post Cold War problems and hopes associated with nuclear weapons. The books bears many of Rhodes's trademarks- it is extremely well-researched and contains sharp portraits of the major players as well as fast-paced accounts of key events that make you feel as if you were there. Rhodes's abilities as a storyteller are still remarkable. This book is relatively slim and does not command the high-octane prose of Rhodes's masterpiece "The Making of the Atomic Bomb" but as usual, Rhodes's authoritative knowledge of nuclear matters provides many revelations and he has a novelist's eye for detail which keeps the reader hooked.

The book can roughly be divided into four parts. The first part concerns the first Gulf War and the dismantling of Iraq's nuclear infrastructure, the second part describes the race to secure nuclear material in the former Soviet republics after the fall of the Soviet Union, the third part briefly talks about South Africa's nuclear ambitions and and then in more detail about attempts to contain nuclear efforts by North Korea and the last part concerns the run-up to the second Gulf War and some final thoughts on the future of nuclear weapons. One striking omission in the book is Iran, and I think readers would have appreciated Rhodes's insightful thoughts on the Iranian nuclear problem.

The first part examines the troubling evidence in the 1980s that Saddam Hussein was trying to build a nuclear capability. Rogue Pakistani scientist A Q Khan had even tried to unsuccessfully sell Iraq a bomb design based on a Chinese weapon. At the same time that the US was providing aid and goodwill to Iraq to support it against Iran in the Iran-Iraq war, it was also unearthing evidence in the form of dual-use equipment shipments and intelligence analysis that Iraq was pursuing enriched uranium. Interestingly, the technology that Iraq was using turned out to be electromagnetic separation, a primitive technology that the US did not initially believe would be used; for nations pursuing nuclear capability, separating uranium isotopes by using centrifuges is much more efficient. Yet electromagnetic separation is exactly the kind of technology that a relatively primitive and cash-strapped economy would pursue. This is a good example of how biases can lead to false conclusions in spite of supporting evidence. Later, Rhodes has pulse-racing accounts of searches for enrichment technology in Iraq conducted by the weapons inspectors of the IAEA and the UN. Even after the inspectors discovered evidence of enrichment in the form of equipment used for electromagnetic separation, this was not yet conclusive evidence of weapons building. Probably the most exciting moment was when, deep down in a small room in a basement, the inspectors discovered a report that did provide such evidence in the form of clear and detailed descriptions of materials and design for an implosion bomb.

The second part of the book deals with the fragmentation of the Soviet Union and the spirited and at times desperate race to acquire nuclear weapons from the former Soviet republics of Ukraine, Belarus and Kazakhstan. There are many heroes in this story which stands as a model of bipartisan cooperation against a serious threat. Among these are David Kay, Hans Blix and Bob Gallucci who were nuclear inspectors and disarmament specialists. Probably the most prominent ones are the Democratic and Republican senators Sam Nunn and Richard Lugar who worked day and night to acquire funds from Congress to secure nuclear material and weapons from the three countries and have them transferred back to Russia. Concomitantly, Secretary of State James Baker hopped from one capital to another, urging the presidents of the new nations to sign the NPT and START using a combination of carrots (in the form of monetary rewards) and sticks (in the form of possible sanctions and threats from Russia). All three nations agreed that they were better off without nuclear weapons, and the result was a transfer of thousands of strategic and tactical weapons back to Russia. A third important and massive effort involved blending down the enriched uranium from Soviet weapons to reactor grade and shipping it back to the US for use in US nuclear reactors; Americans may be amused to know that about 10 percent of their current electricity derived from nuclear energy comes from nuclear weapons that their former foe had targeted against their cities. Curiously, the biggest reformer in this drama was President George H W Bush who orchestrated the largest arms reductions in history (he abolished entire classes of weapons, including missiles with multiple warheads and all ground-based weapons), and he needs to get much more credit for doing this than what has been given to him.

In the third part Rhodes first briefly talks about the dismantling of South Africa's nuclear program, which is a fine lesson for nations wanting to eschew nuclear weapons. In case of South Africa, the same reasons- internal strife, border conflicts and international alienation because of the government's apartheid policies- that provoked the country to acquire weapons also encouraged them to give them up. An uglier reason was their fear in the 80s that the weapons might fall into the hands of the black government.

Rhodes then describes in detail the difficult relationship between the US and North Korea in the context of North Korea's nuclear ambitions. Along the way, Rhodes also provides perspective by noting that the US had mercilessly bombed the North during the Korean War; since then the North Koreans have constantly been in a kind of perpetual state of war, surrounded by giant powers like Russia and China. It's also worth keeping in mind that the US had stationed hundreds of nuclear weapons in South Korea as a deterrent until about 1990. Although these actions by the US do not justify the North's nuclear efforts, they do explain the paranoia and deep sense of insecurity that has fueled North Korea's animosity towards the US. Again, there are heroes in this story, but one singled out by Rhodes is former President Jimmy Carter who went to North Korea of his own volition in 1994 and successfully mediated the Koreans' proposal to stop reprocessing in return for light water reactors; the consequence of this diplomacy was the so-called "Agreed Framework" to regulate North Korea's commercial nuclear program, which unfortunately broke down in 2003 in the face of North Korean non-compliance and disagreements. Since then, North Korea has always had to be kept on a tight leash and there have been several moments of tension between the two countries, but Rhodes's accounts make it clear how diplomacy has averted another Korean War. Rhodes also has succinct discussions of efforts to develop and implement a framework for the CTBT, which was signed by Clinton but unfortunately not ratified by the Senate.

The last part of the book concerns the run-up to the second Gulf War. This story has been told before but Rhodes tells it succinctly and well. Meticulous weapons inspections in Iraq between 1992 and 1998 had unearthed no evidence of a WMD capability, although Iraq had also not furnished clear documentation of the dismantling of its WMD capability. As Rhodes tells it, regime change had already been on the table, especially pushed by neoconservatives like Dick Cheney and Paul Wolfowitz but even contemplated by former Vice President Al Gore. But even after 9/11, it does not seem like Bush was thinking of attacking Iraq. However, as the record indicates, something changed in his thinking in the next two months, and invading Iraq became a concrete strategy in his mind. Rhodes thinks that a major reason for this shift in his thinking may have been the anthrax attacks which followed 9/11. It seems that these attacks really rammed the threat of terrorism home; at one point alarms even went off in the White House and Dick Cheney suspected that he himself may have been contaminated. Nonetheless, as is well-known now, Bush and his associates decided to invade Iraq fueled by the tried and tested strategy of threat-inflation and on evidence that was dubious at best. Rhodes clearly establishes the prevarications of the administration's claims about WMDs in Iraq, based on discredited reports about uranium shipments from Niger to Saddam (reports discredited even by the CIA) as well as Chinese imports of supposed aluminum tubes for centrifuges, which turned out to be parts for short-range rockets. At best Iraq was years behind the difficult goal of building a nuclear weapon, a goal which would have needed extensive operations of enrichment and processing which would most likely have been detected. No matter how you cut it, there was no concrete justification for invading Iraq except one based on ideology and belief. Bush also seriously damaged arms reduction efforts by withdrawing from the ABM treaty, by his belligerent rhetoric against North Korea (which withdrew from the NPT and tested a nuclear weapon in 2006) and Iran, by lifting sanctions on Pakistan (a particularly recalcitrant and prolific proliferator) and by agreeing to supply India (which had not signed the NPT) with nuclear-related equipment. And yet in the midst of this tragedy it is easy to miss Bush's one success in arms control in which he signed major arms reductions with Russia; these reductions brought down the number of warheads on US delivery vehicles from about 10,000 at the end of the Cold War to about 2600.

This brings us to the final, eloquent part of Rhodes's book where he talks about the possible abolishment of nuclear weapons. He describes the very serious problem of nuclear terrorism; in his view, while it may be very difficult for terrorists to use a sophisticated nuclear weapon, it may be much easier for them to acquire enough material for a crude explosive. Even state-owned nuclear weapons are susceptible to accident, miscalculation and misunderstanding. The bottom line is that as long as nuclear weapons are around, there is always a possibility that they may be used. The only, truly final solution for reducing the threat of nuclear weapons is to get rid of them. How do we achieve this? I would have appreciated more detail from Rhodes in this regard, but he describes promising developments. For one thing, simple laws of physics dictate that without nuclear material one cannot make nuclear weapons. So securing nuclear material is key and the Nunn-Lugar initiative has set a worthy bipartisan example for achieving this goal. Many recent initiatives to reduce the threat of nuclear weapons have also been refreshingly bipartisan. Efforts to ban nuclear testing have already been fine-honed for decades, and getting all nations on board the CTBT would mean a lot; in this context Rhodes singles out Australian diplomat Richard Butler and his Canberra Commission for special praise. The fact is that, in spite of nuclear proliferation, there have been hundreds of nations which have found it prudent not to develop nuclear weapons for various reasons (not the least of which is their expense; according to Rhodes it costs the US 50 billion dollars just to maintain its current stockpile of weapons), so there is hope.

In the end though, only political will, strong leadership and international cooperation can rid the world of these terrible weapons. At some point, owning a nuclear weapon needs to become a crime. It is absolutely necessary to stop regarding these weapons as partisan, parochial concerns which can be leveraged to score political points in elections. To underscore this point, Rhodes recounts a fascinating idea put forth by the Scottish writer Gil Elliot in his book "Twentieth Century Book of the Dead". Elliot talks about the international efforts to prevent and cure infectious disease and believes that war should similarly be treated as an international anathema that is to be abolished. Efforts to eradicate disease through public health campaigns crossed boundaries and saw even countries who were otherwise very hostile towards each other mutually cooperating. This was because disease was not seen as some other country's problem but as a common threat. Because of their sheer destructive power, nuclear weapons similarly pose a common threat to all of humanity. Rhodes says that only when nuclear weapons are similarly and completely depoliticized to the extent that infectious diseases are, only when the world sees them not as instruments of aggression and patriotism owned by specific nations but as a common scourge that threatens all of humanity irrespective of our political leanings and differences, only then will we all work together to abolish them.

Miles to go before...

noreply@blogger.com (Wavefunction) — Sun, 29 Aug 2010 01:01:00 +0000

A New York Times article describes a study conducted by the NIH that basically asked scientists to simply sift through the massive evidence of the past twenty years to answer one question; what factors can cause or prevent Alzheimer's disease? The answer is unsurprisingly depressing- there is basically no proven therapy, personal habit, dietary supplement or mental task that correlates with the prevention of AD. AD is still as much a disease without a cure or preventative remedy as it ever was. We have almost as much work to do as Alois Alzheimer would have in 1908.

The bad news about AD has just kept on coming in over the last few years. Part of the reason is the very disappointing verdict on the role of beta-amyloid, reached after dozens of clinical trials which targeted the clump of protein in AD brains and failed to reverse the debilitating effects of the disease. Along with these studies, there has been a panoply of articles suggesting everything from crossword puzzle solving to Gingko biloba extracts that could possibly prevent the disease.

But as the NYT article reports, most of these recommendations are based on faulty 'studies' which are typically called "observational" studies. These studies are essentially accounts of observations made after someone has started on a measure that's assumed to be preventative. In addition, most of these observations are self-reported. Thus, evidence from such observations is spotty at best and is a far cry from the double-blind controlled clinical trials required to establish efficacy. After sifting through the evidence, the NIH study group concluded that they were sure only about one measure- Gingko biloba. And here the verdict was that Gingko biloba does not prevent AD. Apart from this, most other factors touted as preventive measures- including cognitive stimulation, vitamin E and antioxidants- could not be correlated with decreased incidence of AD with any degree of certainty. There's just no good evidence.

Part of the problem is simply the amount of time patients enrolled in trials would have to be observed in order to draw any conclusion about prevention. AD typically emerges around age 50, but its effects become apparent only in the late 60s and early 70s. A true clinical trial to study prevention would probably have to start during the young years and subjects would have to be followed for at least two to three decades, an expensive and complicated endeavor.

Yet the reports cited in the NYT should not be as depressing as they appear. For one thing, many people now think that the real reason none of the therapies for AD are working is simply because they are administered too late. Two new promising studies based on PET scans and spinal taps could make it easier to detect AD earlier and start treatment immediately. Plus, it's precisely the fragmented nature of the reported observations that provides opportunity for studying them further. Also, as depressing as the amyloid-targeting trials were, at least they provide good evidence of something that does not seem to be working. In science, the misses are almost as important as the hits. Finally, it's not like long-term studies cannot be attempted; the famous Framingham study followed the inhabitants of a small Massachusetts town not just over years but over generations to establish the connection between high cholesterol and heart disease. Perhaps a Framingham-style study for Alzheimer's is due.

Until these deep questions are resolved though, AD patients and their families will keep on living their private version of hell and will keep on trying to stave off the terrible malady by trying anything that remotely seems to work. The least we can all do is keep on searching.

From bull horns to under the lens of Anton

noreply@blogger.com (Wavefunction) — Sat, 28 Aug 2010 00:03:00 +0000

In 1989, a young computer scientist named David Shaw was working at Morgan Stanley, one of the first Wall Street firms interested in using computer algorithms for trading. Shaw was an expert in parallel processing, speeding up calculations by executing them in a parallel process over multiple processors. Previously he had been a computer science professor at Columbia University had tried to sell his computer skills to a number of companies, but only Morgan Stanley was genuinely interested. As Shaw started working at the company, he began to think not just of programming strategies but of creative ways in which they could be applied to trading. In a meeting where he was supposed to talk only about his algorithms, he went one step beyond and described better methods for trading using these algorithms. Eyebrows went up in the room. Shaw was essentially seen as overstepping his bounds as a programmer. The higher-ups told him clearly that his job was simply building the computer architecture. He could leave the trading to them. Shaw quit and started his own company. Ten years later, it was one of the most successful hedge funds in the world and Shaw was a billionaire. One can only speculative how much the Morgan Stanley executives cried over the loss they had suffered when Shaw left.

But now D E Shaw is a totally different animal.

One of the most anticipated talks at the ACS meeting was by this Wall Street mover turned pure scientist. He is a remarkable and brilliant man. What other Wall Street hedge fund manager who made billions using mathematical algorithms for trading (and was known as “King Quant” at one point) basically retires from the dizzying world of finance to fully engage himself with computer simulations of proteins? Well, Shaw has done this, and is blazing his way toward some potentially revolutionary research. At the very least it is inspirational to see men with money actually care about basic scientific research.

He heads D E Shaw Research, a company totally separate from the financial powerhouse that has as its long-term goal, a fundamental transformation in the process of drug discovery. As the story goes, Shaw got somewhat bored of making millions and wanted to attack scientific problems that could benefit from the application of advanced computer algorithms. He got his old job as computer science professor at Columbia University and started looking around for the right problem. Fortunately for the field of biochemistry, Shaw started having discussions with a friend of his, the well-known physical chemist Richard Friesner at Columbia who is also the chief scientific advisor for the computational chemistry company Schrodinger. Friesner piqued Shaw’s interest and started giving him little problems in computational chemistry and biology which Shaw solved during his spare time. Finally he realized that MD simulations of proteins which had previously been typically restricted to the nanosecond time range stood a chance of being truly and very significantly useful if they could be expanded to the 10 microsecond-millisecond range, since this is the time scale on which most interesting biological motions such as large conformational changes occur.

Shaw started D E Shaw research and collected a team of highly talented chemists, biologists and computer scientists to tackle the problem. After a decade or so, these efforts have manifested themselves as Desmond, a protein MD program that has vastly accelerated computer simulations of proteins. Desmond essentially relies on many ingenious methods to simplify the calculation of forces and velocities involved in a typical MD computation. It especially calculates the non-bonded forces- the sheer number of which constitutes the bottleneck in these kinds of calculations- with unprecedented efficiency. What is even more remarkable is that Shaw’s group has designed ‘Anton’, a 512 node state-of-the-art machine, a special purpose machine explicitly designed for protein MD and named after Anton van Leeuwenhoek, the legendary 17th century Dutch scientist who trained the microscope on the microbial world and unearthed a wondrous universe teeming with life. Just like the 17th century Anton probed the events of the bacterial world, the 21st century Anton seeks to probe the molecular-level events of the protein world, The machine does only MD, and it does this using a razor sharp scalpel.

To give an idea of the kind of quantum leap Anton provides for MD simulation, Shaw gave some numbers, and I can swear I saw some people who were almost nodding off suddenly become wide awake. According to Shaw, the fastest supercomputer which does parallel processing today can crunch about 200 ns/day for a typical sized protein. Anton surpasses this number by two orders of magnitudes and spews out 17,400 ns or 17 microseconds per day. Such numbers would have been unthinkable a decade ago; until Desmond appeared on the scene, the world record for long protein MD simulations had been held by a group from the University of Illinois, with a total time of 10 microseconds.

So what’s the significance of being able to simulate in this time scale? Tremendous. It’s like the difference between nuclear weapons and the biggest conventional bombs previously used. When nukes arrived on the scene, some politicians like Winston Churchill shrugged them off by thinking that they were “just bigger bombs”. But as the old saying goes, quantity can have a quality all of its own. Nuclear weapons heralded a completely new era of warfare because of the ability of a single weapon to raze a whole city. The basic unit of destruction changed from a human being to entire cities. Desmond and Anton promise such conceptual transformations. As mentioned before, breaking the 10 microsecond barrier is a real turning point since most interesting physiological events happen on time scales of microseconds-milliseconds.

Entering the world of millisecond simulations is like unlocking the door to a rainforest with millions of exotic species that you suspected existed, but which you had no way of viewing and studying. In the last few years, Desmond has been used to study highly significant conduction events in ion channels, has been used to reconcile experimental and conceptual contradictions in the structure of GPCRs, and has been used to study very large conformational changes in kinases. All these events are very slow with respect to conventional MD. Shaw showed some spectacular examples of proteins actually folding and unfolding multiple times. In some cases his group has obtained quantitative agreement with kinetics and NMR experiments.

I think it was the end of the talk which made a few jaws drop. When you have a protein structure and want to find out a small molecule which can modulate its activity, one of the key goals is to first find out where the small molecule binds. With the kinds of time scales available, Shaw can achieve this with a devastatingly straightforward simulation. In a video that appeared a little surreal, he simply let the molecule roam all around the protein surface and find the binding pocket. Like a curious dog sniffing around for the buried bone, the little guy went in and out of crevices and gullies, lingered for some time outside the binding site, and then, with a little hesitation, finally ensconced himself firmly in his cozy home, having surmounted all the challenges of entropy and desolvation that he had to face.

This may not always be the best method to find binding sites and MD admittedly is not going to transform the process of drug discovery by itself, but what we witnessed in that room on Thursday was a different ball game. One in which the ball had been hit out of the park. More surprises should follow.

R B Woodward lives!: ACS Day 2

noreply@blogger.com (Wavefunction) — Tue, 24 Aug 2010 12:34:00 +0000

What kind of a man was Robert Burns Woodward? As a student of his says, "He was a genius. Period. If he walked into the lab and asked for your arm, you would ask, "Which one?"

So much has been said about this legend that not much can be added. But it's worth pondering his contributions. Woodward fine-honed the science of organic chemistry into a precisely rational science and we all stand on his shoulders. Whether it was structure, spectroscopy, or of course, synthesis, his contributions were unmatched. He made molecules whose construction then defied imagination, and even now challenges some of the finest minds in science. And his larger-than-life personality generated a windfall of anecdotes. His obsession with the color blue (with his tie, his office ceiling and his parking space all painted blue), his famous Thursday evening seminars which lasted into the long hours of the night, his heavy drinking which accompanied even his talks, and the talks themselves- those four hour works of art where he filled up long blackboards with exquisitely drawn, multicolor chalk structures- all are the stuff of legend. The man towered above everyone else, even by Harvard standards.

Much of this appreciation was captured by the Robert Burns Woodward symposium organized by the ACS on Monday. It was hard to miss the survivors of a heroic age of organic chemistry sitting in the front row- Jack Roberts, Sam Danishefsky, Jerry Meinwald, Ken Houk, Bill Lipscomb and of course, Roald Hoffmann. People who were looking for historical tidbits found some rare treats. For instance, there was a long video of Woodward describing the synthesis of Vitamin B12 playing outside the room. In addition, Jeff Seeman who is an acclaimed historian of chemistry managed to procure a rather singular video of Woodward (appropriately holding a glass of scotch) being carried on stage for a department function in a sedan chair hoisted on two long wooden beams, like a Pharaoh.

The chair itself was on display next to the stage. In the video, a hirsute graduate student with an unkempt beard is one of the chair-bearers. That hirsute student was Stuart Schreiber, now completely devoid of his former looks, a clean-shaven, balder than bald, world-famous scientist, dressed in his characteristic turtle-neck and sports jacket. The man was mobbed after his talk and asked to pose for photos. I am sure he hates the burden of fame.

The morning began with an endearing introduction by Hoffmann about his former mentor. He described Woodward as a "patterner of chaos" who made organic chemistry intelligible to everyone else. Then there were some fairly technical talks by Yoshito Kishi (mainly) about Cr and Ni-mediated couplings and by Tom Hoye about how Woodward influenced some of his own ideas. There were many memories of Woodward in these talks; how discussions with him used to consist of long periods of silence periodically interrupted by pencil tapping, how his attention to detail was evident in the way he used to compare IR spectra of synthetic and natural material with a pencil and magnifying glass, and how he could hold his alcohol better than anyone else.

This was followed by a lively talk by Robert Williams (Colorado State) who described the recent controversy (albeit one now laid to rest) about Gilbert Stork and the Woodward-Doering-Rabe-Kindler total synthesis of quinine. He talked essentially about Jeff Seeman's marvelous ACIE article and his own follow-up work. As Williams noted, a postdoc named Aaron Smith brought up Seeman's article in a group meeting. Williams said he was "amazed" that nobody had attempted the final conversion of quinotoxine to quinine- the last step of quinine synthesis which Rabe and Kindler were supposed to have performed and which Woodward and Doering took for granted; promptly he assigned the project to Smith (just another project that a beleaguered postdoc needs). It's worth taking a look at Williams's paper and to read about some of the obstacles he and Smith had to overcome, especially in investigating "aged" aluminum powder which gave different results. They actually used only reagents and conditions available in 1944 to make sure they could reproduce Rabe and Kindler's work.

And then, the really controversial piece by Jeff Seeman, the piece de resistance about E J Corey's "contribution" to the Woodward-Hoffman rules. The word "plagiarism" in the title of the talk guaranteed a full room. In a sense the talk was not as controversial as everyone thought since Seeman never really answered the question ("Was plagiarism involved in the development of the Woodward-Hoffmann rules?") with a simple yes or no. However, he also made it clear that it may well be impossible to answer the question this way. What was clear is that he has had only one or two chances to get E J Corey's side of the story. On the other hand, Corey himself has made his view about the matter quite clear. In his Priestley Medal acceptance speech, he quite clearly and matter-of-factly said that he gave Woodward a suggestion about electrocyclic reactions that involved looking at the symmetry of the orbitals. More provocatively, he made this point much more emotionally in two letters to Hoffmann in 1981 and 1984, where he stopped short of accusing both Hoffmann and Woodward of blatant dishonesty and plagiarism. The way Corey tells the story, he stopped by Woodward's office on an evening, Woodward asked him the question, Corey gave Woodward a suggestion, and then Woodward apparently incorporated Corey's suggestion into his own framework without giving due credit to Corey. Woodward also clearly told Hoffmann that Corey had played no role in the development of the rules. One interesting point that Seeman made was that many other organic chemists were thinking along the same lines as Woodward and Hoffmann around this time, as evidenced from publications. So perhaps the right question is; why didn't anybody else come up with the Woodward-Hoffmann rules? It's also interesting to note, as recounted by Hoffmann in his Angew Chem article, that Corey employed electrocyclic reactions to control stereochemistry in his synthesis of a compound named dihydrocostunolide, which he published a year or two after the alleged appropriation of his idea. If he was really keen on making his contribution known, why didn't he talk about the conservation of orbital symmetry in his paper? Or was he afraid it would have just made it look like he was piggybacking on the Woodward-Hoffmann concept? Many such little and not so little questions remain unanswered. There are other interesting anecdotes. According to Corey's own account, his relationship with Woodward cooled to a strictly business relationship after he thought Woodward failed to give him due credit. In spite of this, Woodward warmly recommended Corey as the top contender for the Cope Award.

Seeman also had some interesting statistics about a study he conducted regarding the assignment of credit in publications. He and a colleague polled 600 academic chemists and asked them whether there was a time when they thought they hadn't been given credit as an author on a paper. About 50% said yes. Most people also said that they had not been given credit by another faculty member from their department rather than their own advisor. It's also worth highlighting another question Seeman asked to the respondents, whether they would include someone who had contributed a key intellectual idea and nothing more either as an author or in the acknowledgments of a paper. The majority of respondents (42%) agreed that such a person should be included in the acknowledgments, although a visible number (21%) also agreed that such contributors should be listed as co-authors. These are interesting statistics. I think we have all faced situations where, in group meetings, seminars or even in casual discussions down the hall, we have provided important suggestions to a student, colleague or faculty member. However, we may then not have had anything to do with the actual execution of the idea. The question is; in what way then, if at all, should our contribution be acknowledged by the person capitalizing on our idea? Just something to ponder.

In the end as Seeman narrated, the story might never be unravelled, partly because it goes far beyond the immediate topic at hand and treads into questions about the genesis of ideas, personal ambitions, academic prestige, scientific communication, the ways in which human beings understand each other and the myriad ways in which we misunderstand each other.

Finally, does it matter? Both Woodward and Corey's place in the history of chemistry is assured beyond a shade of doubt. Whatever people's opinions about E J Corey may be, you would not find a soul who denies that he is an undisputed giant of chemistry. Woodward, Hoffmann and Corey all won their medals and had extraordinary careers. Hoffmann became known not just as a chemist but also as a man of letters, and Corey is probably the greatest chemist alive today. Yet the story will continue to intrigue us, simply because it involves so many elements of human fallibility, folly and triumph which we encounter in all aspects of the human experiment.

Does RBW still live? In more than one way, yes! Stuart Schreiber who gave the last talk on cancer therapeutics started by showing some revealing pages from his graduate school notebook with RB's scribblings. RB had drawn what we today know as graphene, and there were some figures in which he had pondered inserting nitrogen atoms into graphene. Schreiber strongly believes that RB was getting seriously interested in materials chemistry towards the end of his life, and he also reminded everyone that Nobel Prizes were won for fullerenes and conducting polymers. Had RB started to foreshadow some of this work? Would he have become the world's preeminent materials chemist after he had conquered the realm of natural products? We will never know.

What we do know for sure is that the world as a whole will always be grateful to Roald Hoffmann, E J Corey and R B Woodward for all they have done. Among the thicket of controversies, personal rivalries and ambiguous interpretations, this fact will always stand as the one bright, shining light in the dark jungle of historical analysis. Science always wins.

ACS Day 1

noreply@blogger.com (Wavefunction) — Mon, 23 Aug 2010 00:56:00 +0000

Not much to write about since I spent the better part of the day sweating over my own presentation. At the last moment I ran into a problem; they are recording presentations and for this purpose they needed me to upload my presentation on to a PC. A PC!!! My keynote presentation was as alien to the PC as General Tso's chicken would be to a Chinese farmer in rural China. Fortunately a maintenance guy was on hand and he copied my presentation to his flash drive and promised that it would be powerpointed and synced to my voice later. The end product is going to be very unpredictable.

A couple of other things:

1. Starbucks located in the Westin next door. Hallelujah.

2. I really hope the food court at the convention center is going to be open the rest of the week since the nearest restaurant is at least a 10 min walk. Plus, with a couple of thousand souls descending on the city, any bartender worth his fish and chips would be swamped (as the one today was) and I was lucky to find a place even at the bar.

3. Segways on a first come first serve basis? It takes longer than the average talk to walk from one talk to another. The alternative is to dress up like a 80-year old lady with a cane since a few lucky seniors are being ferried across by those little electric carts from the airport. I am seriously contemplating this.

Casually overheard: in the restaurant, in the restroom and down the hall

noreply@blogger.com (Wavefunction) — Mon, 23 Aug 2010 00:44:00 +0000

"Didn't they make Einsteinium?"..."No, you SOLVATE the excited state"..."I did a really bad-ass Grubbs on that baby"..."You can molecular dynamics that to hell and it still won't help".

Yes, ACS meetings can be pretty nice. I almost forgot.

Woodward-Hoffman-Schmoffman?

noreply@blogger.com (Wavefunction) — Thu, 19 Aug 2010 21:38:00 +0000

Next week I am attending and giving a talk at the ACS National Meeting in Boston. Lots of interesting presentations, but the unusual title of one talk in particular caught my eye:

"Was plagiarism involved in the development of the Woodward—Hoffmann rules?"

Jeffrey I. Seeman Ph.D.

That sounds like fun! I am guessing the answer is going to be 'no'. It's in Room 205A/B on Monday, August 23rd.

Briefly noted

noreply@blogger.com (Wavefunction) — Mon, 16 Aug 2010 15:14:00 +0000

1. At last, the crystal structure of ribose

2. The long-sought connection between tau and amyloid protein in Alzheimer's disease?

3. Design of a cell-penetrant peptide (CPP) based on cytochrome C which induces apoptosis by sequestering the protein nucleoporin

4. The fate of organic chemists (and chemists in general) in industry. A depressing but useful discussion on In The Pipeline.

Open-sourcing Alzheimer's diagnosis

noreply@blogger.com (Wavefunction) — Fri, 13 Aug 2010 13:45:00 +0000

In the middle of all that disappointing news about failed treatments targeting beta-amyloid, here's some silver lining. A lot of people think that the real reason all these drugs are not fighting AD is not because they are ineffective per se but because they are administered too late, long after the disease has manifested itself. Thus the logical step toward making these therapies more effective would be in detecting AD earlier. In the last few months, a slew of articles has detailed several techniques for diagnosing AD early which look promising, from better brain imaging to spinal taps. An article in today's New York Times looks at the integrated effort that has spawned these developments. It turns out that the effort has come about from several government agencies, universities, non-profit organizations and imaging and pharmaceutical companies collaborating to find early biomarkers for AD. The joint initiative has pooled together several million dollars from each contributor. As everyone wisely realized, AD is much too complex to be tackled by single research entities (what disease isn't?). As one participant said:

"We all realized that we would never get biomarkers unless all of us parked our egos and intellectual-property noses outside the door and agreed that all of our data would be public immediately.”

"Parking their egos" outside would be necessary for the diverse and large studies required to gain insight into true AD biomarkers.

“The problem in the field was that you had many different scientists in many different universities doing their own research with their own patients and with their own methods,” said Dr. Michael W. Weiner of the San Francisco Department of Veterans Affairs, who directs ADNI. “Different people using different methods on different subjects in different places were getting different results, which is not surprising. What was needed was to get everyone together and to get a common data set.”
But that would require a huge effort. No company could do it alone, and neither could individual researchers. The project would require 800 subjects, some with normal memories, some with memory impairment, some with Alzheimer’s, who would be tested for possible biomarkers and followed for years to see whether these markers signaled the disease’s progression.

The problem is of course is that it can be tricky as hell to distinguish true biomarkers from spurious ones (the old problem of distinguishing correlation from causation). It would take some time to zero in on those biomarkers that truly signal the onset of the disease. But this bit of news is gladdening for two reasons; firstly because it indicates that people are perhaps moving away from the obsession with targeting amyloid (which nonetheless continues to be a fascinating entity), and more importantly because it indicates that there are still people willing to park their egos outside the door and publicly collaborate to address a very complex medical challenge. Hopefully this endeavor should provide inspiration for tackling other diseases.

Chembark is back!

noreply@blogger.com (Wavefunction) — Thu, 12 Aug 2010 12:13:00 +0000

Paul Bracher is back from his self-imposed cyber-celibacy! Stay tuned.

Briefly noted

noreply@blogger.com (Wavefunction) — Mon, 09 Aug 2010 19:42:00 +0000

1. Snake venom protein specificity explained through differences in protein dynamics probed by molecular dynamics simulations.

2. A 'new' interaction discovered in protein structures? The lone pair of a C=O oxygen can interact with the anti-bonding orbital of another C=O bond. Do we need to incorporate this interaction into force fields yet?

3. Rosetta performs another impressive feat, this time designing a Diels-Alderase enzyme from scratch that performs a bimolecular DA reaction

4. Sir Charles Mackerras, one of the finest interpreters of Mozart, is dead at 84. I was not aware that he played such a prominent role in bringing Leos Janacek's operas to the West.

5. An extremely well-written and comprehensive account of the (healthy) controversy over the exact binding site of drugs binding to the M2 proton channel protein in the influenza virus. As the post says, this is exactly how good science progresses, and we all benefit from such spirited to-and-fro.

Remember

noreply@blogger.com (Wavefunction) — Fri, 06 Aug 2010 14:27:00 +0000

From Nobel Laureate Kenzaburo Oe:

Sixty-five years ago, after learning that a friend who was reported missing after the bombing of Hiroshima had turned up in a hospital there, my mother put together a meager care package and set out from our home in Shikoku to pay a visit. When she returned, she shared her friend’s description of that morning in August 1945.

Moments before the atomic bomb was dropped, my mother’s friend happened to seek shelter from the bright summer sunlight in the shadow of a sturdy brick wall, and she watched from there as two children who had been playing out in the open were vaporized in the blink of an eye. “I just felt outraged,” she told my mother, weeping.

Even though I didn’t fully grasp its import at the time, I feel that hearing that horrifying story (along with the word outrage, which put down deep, abiding roots in my heart) is what impelled me to become a writer. But I’m haunted by the thought that, ultimately, I was never able to write a “big novel” about the people who experienced the bombings and the subsequent 50-plus years of the nuclear age that I’ve lived through — and I think now that writing that novel is the only thing I ever really wanted to do.

In Edward W. Said’s last book, “On Late Style,” he gives many examples of artists (composers, musicians, poets, writers) whose work as they grew older contained a peculiar sort of concentrated tension, hovering on the brink of catastrophe, and who, in their later years, used that tension to express their epochs, their worlds, their societies, themselves.

As for me, on the day last week when I learned about the revival of the nuclear-umbrella ideology, I looked at myself sitting alone in my study in the dead of night . . . . . . and what I saw was an aged, powerless human being, motionless under the weight of this great outrage, just feeling the peculiarly concentrated tension, as if doing so (while doing nothing) were an art form in itself. And for that old Japanese man, perhaps sitting there alone in silent protest will be his own “late work.”

Humans beat computers in predicting protein structures

noreply@blogger.com (Wavefunction) — Thu, 05 Aug 2010 14:04:00 +0000

I was going to first describe Rosetta in a post, but a rather cool paper related to the program which appeared in Nature yesterday makes me jump the gun.

In a nutshell, Rosetta tries to predict the structure of proteins from amino acid sequence by inserting fragments from known protein structures and doing many rounds of side chain torsional angle and rigid-body energy optimization. It uses a scoring function to rank the resulting structures that uses empirically derived hydrogen bonding, hydrophobic burial and desolvation terms. Detailed description will have to await the next post since yesterday's paper is not about Rosetta per se.

Instead the paper talks about a program named FoldIt which essentially asks relatively untrained computer gamers to address the protein folding problem. Gamers are asked to tweak, pull, freeze and rotate parts of an incorrectly folded structure to try to twist it into the correct structure. The interface looks like the picture above. Data from a total of 57,000 gamers was pooled. The gamers were driven to solve the problem by the usual incentives of competition and co-operation. Each set of movements would lead to an increase or decrease in a score, with the goal being to find the correct folded structure corresponding to the minimum score. The corresponding set of operations in Rosetta would involve hydrophobic burial, hydrogen bond formation and breakage, helix rotation and other related movements. The project essentially pitted Rosetta versus the gamers.

The results were striking. In a significant number of cases, the gamers actually outdid Rosetta. The reasons are very intriguing and- in an age where computers seem to have unlimited power over our lives- generally testify to the advantages of humans being over computers. For instance in one case, the gamers had to first unravel significant parts of the protein leading to a sharply unfavorable score and then again re-fold it, leading to a correct structure. Rosetta would not attempt the first operation because of the sharp increase in score. This is a classic example of long-term strategy. Unlike computers, humans can make seemingly bad short-term decisions that ultimately lead to good results; we observe this process in many aspects of daily life, from stock market traders taking risks because they see favorable returns later, to politicians making unpopular choices because they think these choices will eventually lead to a popular outcome. Unlike humans though, it is very difficult for a computer program to do long-term planning, and this example illustrates not only the advantages that human intuition can have but also identifies gaps in a program like Rosetta which can possibly be filled.

Another example where the humans outdid the computers was when presented with a set of 10 incorrect structures. Humans generally chose the structure closest to the given structure, whereas Rosetta picked another structure. The main point here is that simple visual clues can sometimes trump complicated decision-making (although they can also mislead). More generally, the results underscored the fact that gut feelings and mere inspection can sometimes lead to successful results.

The one case where the humans did not do as well as Rosetta was in addressing the "classic" protein folding problem, where the challenge was to predict 3D structure from sequence alone. In this case, the sheer amount of conformational space to be searched thwarts success, and there are also no visual cues to guide the process unlike before. The key value of computer approaches which can rapidly pare down the conformational space becomes evident in this example.

So since humans outdid the computer in many cases on the basis of intuition, this must be one super-smart group of biochemists, right? Au contraire! One of the most compelling facts was that most of the gamers in fact not only lacked a formal background or PhD. in biochemistry, but also lacked a formal background in science. Relatively few had college degrees, let alone more advanced ones. For instance there is a profile of a woman in the video below who works in a physical therapist's office, who says that after coming home she feels like a different person when she plays the game. This is great. The examples strikingly illustrates that even untrained humans can possess skills that may be difficult to program into a computer.

It remains to be seen if these results can be extrapolated to large-scale trials, but this very intriguing study perhaps illustrates the general principle that cracking a problem as complex as protein folding is going to require a diverse set of skills, from Monte Carlo searching to gut feelings.

Cooper, S., Khatib, F., Treuille, A., Barbero, J., Lee, J., Beenen, M., Leaver-Fay, A., Baker, D., Popović, Z., & players, F. (2010). Predicting protein structures with a multiplayer online game Nature, 466 (7307), 756-760 DOI: 10.1038/nature09304

Shattering the nuclear sword

noreply@blogger.com (Wavefunction) — Wed, 04 Aug 2010 18:01:00 +0000

"Every man, woman and child lives under a nuclear sword of Damocles, hanging by the slenderest of threads, capable of being cut at any moment by accident, or miscalculation, or by madness. The weapons of war must be abolished before they abolish us.”- John F. Kennedy, speech to the UN, September 1961.

"Countdown to Zero" is one of the best accounts of the dangers of nuclear weapons for the layman that I have recently seen. The film which opened last week takes a comprehensive yet succinct look at the risks posed by nuclear weapons, and is set against the backdrop of John F. Kennedy's speech to the United Nations in which he quoted the words cited above. JFK talked about a "Sword of Damocles" hanging on our head that is secured by a flimsy thread. As the film emphasizes, the most important operative words in Kennedy's speech are "accident, miscalculation or madness" which can all cut the thread holding the sword. To illustrate how this could happen, the film showcases interviews with leading arms control experts and policy personnel, including former CIA agent Valerie Plame, Harvard professor Matthew Bunn, nuclear terrorism expert Graham Allison, WMD expert Joseph Cirincione and world leaders like Mikhail Gorbachev and Tony Blair.

The fact is that no matter how responsible the leaders of countries with nuclear weapons may be and how well-protected the weapons may seem, the extremely complex nature of the system always increases the chances of miscalculation, accident or madness. The film gives concerning examples. For instance, a few years ago, nuclear weapons instead of regular ones were loaded on a plane in North Dakota and flown almost halfway around the country without anyone noticing it. The Cuban Missile Crisis is of course well-known, lesser known are the Palomares incident and half a dozen others when nuclear weapons were accidentally dropped from mid air. Fortunately none detonated. But the danger is pervasive and the film also recounts some chilling events. The most heart-stopping is an incident in 1995 recounted by Cirincione, when the Russians mistook the flight of an experimental rocket from Norway for a nuclear launch. The codes were ready, everyone in the Russian hierarchy was convinced, and all that remained to launch a nuclear strike against the US was President Yeltsin's approval. Thankfully for the world, Yeltsin was "not drunk" and he did not trust the officials' judgment enough, leading to a narrow brush with catastrophe. The problem is that the complex protocols embedded in the use of nuclear weapons allow much opportunity for misunderstandings and accidents and very little time for response and corrective action. Even a President would have typically no more than a few minutes to make a decision, thus increasing the possibility of triggering armageddon. The simplest and most ludicrous of causes can set off false alarms; in one case, the setting off of a nuclear alert was the result of a malfunction in a single computer chip costing less than a dollar.

One of the most jaw-dropping instances I remember was from Richard Rhodes's book. Zbigniew Brzezinski, Jimmy Carter's National Security Advisor, was woken up in the middle of the night and told that there were 1500 Soviet nuclear missiles headed for the US. As Brzezinski was contemplating what to do next, the caller called back and said that the number of missiles had been upgraded to 15000. Hearing this, Brzezinski just sat on his bed; there would be no point in alerting anyone. Of course, it turned out to be "computer malfunction".

Apart from such misunderstandings, the other reason why nuclear weapons pose such a great danger is of course because they may fall into the hands of terrorists, and deterrence does not apply to such stateless actors. Al Qaeda has been trying to get their hands on nukes for years. What makes the situation worse is the relatively easy accessibility of enriched uranium in the former Soviet Union. After the Cold War ended, many nuclear facilities in the former Soviet republics found themselves orphaned, severed from central control, with their workers out of a job. While many of the facilities were later secured with US cooperation, many others were ludicrously insecure, with barely a padlock preventing access to nuclear material; in the words of a former Soviet official, "potatoes were guarded better". Selling a few grams of uranium to potential buyers would allow impecunious laid-off workers from these facilities to make a lucrative buck. The film documents that there have been literally dozens of instances when former nuclear workers have been caught trying to smuggle a few grams of nuclear material across borders in Russia and Central Asia. In addition, countries like Iran, North Korea and Pakistan are happy to trade nuclear-related technology to wannabe buyers.

This nuclear material is notoriously hard to detect. As the film says, smuggling a few kilograms of enriched uranium by shielding it in a lead pipe is child's play. This is mainly because the relatively weak radiation from uranium can be almost completely shielded by lead, but also because this uranium could be hidden in any one of a whopping 100,000 shipping containers entering the US every single day. Finding a few kilos of U-235 in a heavily shielded lead casing in one of these countless containers is an unimaginably difficult problem to solve. Set the detectors on high and one would not detect the low-intensity radiation. Set it on low and one would detect almost everything else (including fruits, papers and wood) which emit comparable ambient levels of radiation.

If terrorists manage to get past the most difficult step of acquiring nuclear material, they can easily build a crude nuclear bomb. Plus, paraphrasing Churchill, terrorists don't have to do their best, they just have to do enough. Exploding a crude bomb in the port itself would not be what they have in mind, but it would still be enough to bring about chaos and panic, possibly collapsing the financial and economic system of a country.

So what can be done to address this life-threatening problem? One of the biggest truisms about nuclear weapons which separates them from other WMDs is that if you don't have uranium or plutonium, you cannot build these weapons, period. Thus in theory, you completely solve the problem if you secure the material. Programs for securing material from the former Soviet republics have been instituted for years, but funding has embarrassingly been a problem. Plus there is no accurate estimate of how much material may have been stolen after the Soviet Union collapses. Securing this material would be the first thing to do. Secondly, countries who want to peacefully pursue atomic energy must be provided nuclear material by an international body under the strictest of safeguards.

But most importantly, there is one almost perfect solution which there is no getting around: reduce the nuclear arsenals of the world to zero. Nada. Zilch. There is no doubt that the US and Russia which still stock the lion's share of nukes should take the lead, a point which has been belabored often to scant effect. This should especially be ludicrously easy for the US which still has thousands of nukes on hair-trigger alert and which has conventional forces that could easily overwhelm any other country's defenses and offenses. If there is one country that does not need any nuclear weapons, it's the US, followed by Russia. The psychological impact of the US renouncing every single nuclear weapon would be hard to overestimate (Nixon did it with chemical and biological weapons in the 70s). It would be tremendous and would offer the US an unprecedented moral authority to ask others to do the same. While it may not be easy for countries like India and Israel which share extensive boundaries with unstable and dangerous regimes, such an act will signify huge potential. This was a dream that President Reagan often talked about. As idealistic as it sounds, it should be feasible at least for the US. Most refreshingly, amid all the partisan bickering that we keep hearing about, such an initiative has gained traction with a wide swathe of influential statesmen from both parties. In a compelling document last year, several former highly influential bipartisan officials like Henry Kissinger, George Schultz, William Perry and Sam Nunn called for the abolishment of nuclear weapons. President Obama has latched on to this dream. It remains to be seen what he actually does about it.

As JFK said in his speech, "the weapons of war must be abolished before they abolish us". In 1986, during the very promising Reykjavik meeting when Reagan and Gorbachev came within a hairsbreadth of getting rid of all nuclear weapons, Reagan told Gorbachev about a dream that seems straight out of a movie. He said that once the world has decided to get rid of all nuclear weapons, he and Gorbachev would meet again in Reykjavik, each holding the last nuclear missile in their hands. They would both be so old that they would hardly recognize each other. Gorbachev would squint at Reagan and say "Ron, is that you"?. And Reagan would say, "Mikhail?". And then they would both destroy the last two nuclear bombs on the planet, and the whole world would have a giant party.

We will have the champagne ready.

Trailer:

Curbing the combinatorial catch

noreply@blogger.com (Wavefunction) — Tue, 03 Aug 2010 19:44:00 +0000

The 'combinatorial explosion' problem generally refers to the difficulty of locating a unique solution to a given problem when the potential space of solutions to be searched is astronomically large. It is found in many areas of science but most notably in protein folding where it takes the name of "Levinthal's Paradox". Biochemist Cyrus Levinthal pointed out in the 60s that if a given sequence of amino acids were to explore every possible conformation for each of its amino acids, even a small protein of 100 amino acid residues or so would take a time longer than the age of the universe to find the correct folded structure.

The paradox is clearly not a paradox since nature has solved the problem of protein folding countless number of times since life began on this planet (this is the protein-centric version of the anthropic principle). Thus, the combinatorial 'problem' is not a problem so far as we know that a robust and tried-and-tested solution exists and in fact has been used by nature to stunning effect. The problem is really to figure out the devilish details of this solution. In the past 30 years or so scientists have employed a battery of experimental and theoretical techniques to tackle the issue. Many important insights have revealed that understanding the factors that dictate the self-assembly of proteins can lead to great insights into the problem. Probably the foremost among these factors is the hydrophobic effect, which productively buries greasy chemical functionalities in the interior of proteins utilizing the multiple driving engines of favorable desolvation, entropic expulsion of water and weak packing-induced interactions. Other important factors ubiquitously used by nature include hydrogen bonds and salt bridges.

The key insight in tackling the problem has been to realize that protein folding or protein-protein interactions or indeed, all the myriad biomolecular interactions that occur in the cellular milieu, do not arise 'by chance'. Once we get past this stumbling block, things make a lot of sense. Chance events undoubtedly keep on happening, but nature preferentially preserves the consequences of certain events. Thus, similar motifs which have been successfully used for certain proteins are used for others. Nature does not need to keep on searching all of conformational space again and again for generating new structures. The analogy would be in designing a new house based on existing structures like bricks, arches and beams rather than designing it from scratch. A Victorian Englishman coined a word for this process of preservation of favorable elements leading to new biological entities a hundred and fifty years ago- natural selection. Thus, the protein folding problem can be immediately demystified when one realizes that natural selection keeps on using recurring motifs to build new structures. Far from being a chance event, the complexity of life can be explained by the re-use of pre-existing structures to build complexity. It may seem highly improbable and miraculous, but Darwin's genius was to provide a mechanism for precisely explaining this illusion of 'design', both on macro and molecular scales. It no longer seems improbable, but instead offers us a tool of incomparable power to peek into the heart of complex biological phenomena.

From a chemist's point of view, natural selection at the molecular level takes the form of the preservation of low-energy conformations of biomolecules that may possess other qualities such as stability, catalytic proficiency and rapid replication. Such chemical entities (think 'DNA') will persist and proliferate and they will be used in multiple designs. Consider coiled-coil structures with their typical seven-residue amino acid motifs or the catalytic triad that cleaves peptide bonds in proteases. Or think of something that's bleedingly simple- the phosphate group which, by virtue of its remarkable qualities of 'transient stability' to hydrolysis, proves to be the perfect connection for life's lego pieces. Once nature hit upon such designs, they could be easily employed in many different structures, dramatically reducing the amount of functional space to be searched. From a chemical perspective, the key property of these favored motifs is self-assembly which is driven by many well-understood physicochemical factors such as the aforementioned hydrophobic effect. Self-assembly, surely one of the greatest inventions of the laws of physics and chemistry, took the problem of the origin of life from miraculous impossibility to tantalizing possibility.

If nature can use pre-existing functionalities to solve the protein folding problem, why can't we do the same? Indeed, many theoretical approaches to protein folding have adopted this kind of approach. Probably the foremost algorithm for predicting protein folding today is a suite of programs called Rosetta which was originally developed by David Baker's group at the University of Washington. In a competition to predict protein structures in 2001, the program did so well that it was compared by a very famous computational chemist named Peter Kollman to Babe Ruth's world record, when even the second-best competitor was woefully lagging behind.

In the next post we will take a look at this program and why it works so successfully.

Models, laws and the limits of reductionism

noreply@blogger.com (Wavefunction) — Wed, 28 Jul 2010 14:43:00 +0000

I am currently reading Stuart Kauffman's "Reinventing the Sacred" and it's turning out to be one of the most thought-provoking books I have read in a long time, full of mind-bending ideas. Kauffman who was originally trained as a doctor was for many years a member of the famous Institute for Complexity in Santa Fe, which is a bastion of interdisciplinary research.

Kauffman is a kind of polymath who draws upon physics, chemistry, biology, computer science and economics to essentially argue the limitations of reductionism and the existence of emergent phenomena. He makes some fascinating arguments for instance about biology not being reducible to specific physics. One of the main reasons this cannot be done is because the evolution of complex biological systems is contingent and can follow any number of virtually infinite courses depending on slightly different conditions; according to Kauffman, this infinity is not just a ‘countable infinity’ but an ‘uncountable one’ (more on this mind-boggling distinction later). Biological systems are also highly non-linear and full of feedback and 'surprises' and these qualities make their prediction not just very difficult in practice but even in principle.

I am sure I will have much more to say about Kauffman’s book later, but for now I want to focus on his argument against reductionism based on what is called the ‘multiple platform’ framework. Kauffman’s basic thesis draws on an argument made by the Nobel laureate Philip Anderson. Anderson wrote a groundbreaking article in Science in 1972 extolling the limits of reductionism. To illustrate the multiple platform principle, he talked about computers processing 1s and 0s and manipulating them to give a myriad number of results. The question is: is the processing of 1s and 0s in a computer uniquely dependent upon the specific physics involved (which in this case would be quantum mechanics)? The answer may seem obvious but Anderson says that it’s hard to make this argument, since one can also get the same results from manipulating buckets that are either empty (0s) or filled with water (1s). Thus, the binary operations of a computer cannot be reduced to specific physics since they can be modeled by ‘multiple platforms’.

Another example that Kauffman cites is of the Navier-Stokes equations, the basic equations of fluid dynamics. The equations are classical and are derived from Newton’s laws. One would think that they would be ultimately reducible to the movements of individual particles of fluid and thus to quantum mechanics. Yet as of today, nobody has found a way to derive the Navier-Stokes equations from those of quantum mechanics. However, the physicist Leo Kadanoff has actually ‘derived’ these equations by using a rather simple ‘toy world’ of beads on a lattice. The movement of fluids and therefore the equations can be modeled by moving the beads around. Thus, we again have an example of multiple platforms leading to the same phenomenon, precluding the unique dependence of the phenomenon on a particular set of laws.

All this is extremely interesting, but I am not sure I follow Kauffman here. The toy world or the bucket brigades that Kadanoff and Anderson talk about are models. Models are very different from physical laws. Sure, there can be multiple models (or platforms) for deriving a given set of phenomena, but the existence of multiple models does not preclude dependence on a unique set of laws. A close analogy which I often think of is from molecular mechanics. A molecular mechanics model of a molecule assumes the molecule to be a classical set of balls and springs, with the electrons neglected. By any definition this is a ludicrously simple model that completely ignores quantum effects (or at least takes them into consideration implicitly by getting parameters from experiment). Yet, with the right parametrization, it works well-enough to be useful. There could conceivably be many other models which could give the same results. Yet nobody would make the argument that the behavior of molecules modeled in molecular mechanics is not reducible to quantum mechanics.

Kauffman’s argument that the explanatory arrows don’t always point downwards because one cannot always extrapolate upwards from lower-level phenomena is very well-taken. Emergent properties are surely real. But at least in the specific cases he considers, I am not sure that one can make an argument about phenomena not being reducible to specific physics simply because they can be derived from multiple platforms. The multiple platforms are models. The specific physics constitutes a set of laws, which is quite different.

The jewel of physics faces the 4% challenge

noreply@blogger.com (Wavefunction) — Wed, 14 Jul 2010 14:14:00 +0000

The size of the proton has shrunk by 4%, or so they tell us. The research which was published in Nature and has created waves apparently interrogated the proton with a much more reliable subatomic entity, the muon, which led to a more accurate result. The result of course testifies to the incredible power of modern science to divine such unbelievably small numbers.

But according to a NYT article, this might mean that the "jewel of physics", quantum electrodynamics, may be in trouble. QED which was developed by Richard Feynman and others is the most accurate theory known to science, and has calculated the magnetic moment of the proton to an accuracy of ten significant figures with respect to experiment. As Feynman himself said, this is like calculating the distance between New York and New Orleans to within the width of a hair.

The present measurement could shake up this success a bit according to the article:

When that new radius, which is 10 times more precise than previous values, was used to calculate the Rydberg constant, a venerable parameter in atomic theory, the answer was 4 percent away from the traditionally assumed value. This means there are now two contradicting values of the Rydberg constant, Dr. Pohl explained, which means there is either something wrong with the theory, quantum electrodynamics, or the experiment.

“They are completely stunned by this,” said Dr. Pohl of his colleagues. “They are working like mad. If there is a problem with quantum electrodynamics this will be an important step forward.”

The late Caltech physicist Richard Feynman called quantum electrodynamics “the jewel of physics,” and it has served as a template for other theories.

One possibility is that there is something physics doesn’t know yet about muons that throws off the calculations.

Or perhaps something we just don’t know about physics. In which case, Jeff Flowers of the National Physical Laboratory in Teddington in Britain pointed out in a commentary in Nature, a new phenomenon has been discovered not by the newest $10 billion collider but by a much older trick in the book, spectroscopy.

“So, if this experimental result holds up, it is an open door for a theorist to come up with the next theoretical leap and claim their Nobel Prize,” Dr. Flowers wrote.

In other news, a physicist has postulated that gravity is not really a fundamental force but could be a manifestation of the second law of thermodynamics.

Who said challenges do not abound in modern physics!

Computational modeling of GPCRs: What are the challenges?

noreply@blogger.com (Wavefunction) — Mon, 12 Jul 2010 14:05:00 +0000

GPCRs are extremely important proteins both for pure and applied science research, but they are also very difficult to crystallize and hence structural information on them has been sparse. Naturally in such a case, computational modeling can be expected to be of great value of providing insight into GPCR structure and function. However, even though progress has been impressive, such modeling still has to overcome many challenges. A recent review lists some of them.

Firstly, in the absence of crystal structure, homology modeling wherein a sequence for an unknown structure is 'threaded' through that of a known one is well-established as a valuable technique. However the technique is tricky. First and foremost one has to get the right sequence alignment between the target and the template. As the article notes, recent studies have suggested that using multiple structures for alignment instead of a single one provides better results. Particularly noteworthy is this detailed study. Once a homology model has been obtained, it must be meticulously examined, both for internal consistency (bad contacts, incorrect hydrogen bonding interactions etc.) and for its agreement with experiment. Data from cross-linking studies and mutagenesis can be used to achieve this. A recent promising development has been termed 'ligand-supported homology modeling'. In this process, topographical protein-ligand interaction data from mutagenesis and other studies is used to limit the number of homology models. Such data-driven homology modeling is becoming increasingly popular.

Once a good homology model has been obtained, many things can be done with it. Molecular dynamics (MD) simulations provide a very valuable avenue for exploring protein motion and be used to detect structural features not obvious in static models. A recent MD simulation of the beta-adrenergic receptor helped to resolve discrepancies between biochemical and structural observations. MD simulations can be used to investigate protein dynamics and to refine the models. Several challenges present themselves during this procedure. Firstly, while helices in GPCRs can be well-modeled, loops (of which there are six- three intracellular and three extracellular) are much harder to model because of their higher flexibility and because they are often ill-resolved in crystal structures. Unfortunately, it's these loops which are important ligand-interacting elements, so getting them right is key. Recently developed algorithms for loop-refinement based on either first-principles energy minimization or by statistical modeling based on a database of known loop conformations have been used in getting loops right. Also, state-of-the-art long MD simulations spanning several microseconds can be used to model large-scale structural changes in GPCRs.

There are still immense challenges still to be overcome in understanding GPCRs. One of the biggest concerns the cycling between several inactive and active states (and not just one active and one inactive state) that present often conflicting features that can be subject to varying interpretation. For instance, for class A GPCRs (which is the largest class), it has been well-established that activated states involve the breakage of the "ionic lock", a salt bridge between arginines and glutamates on transmembrane helices 6 and 3. Breaking this lock allows TM6 to shift away from TM3 and towards TM5, a hallmark of GPCR activation. Yet the MD study on the beta2 cited above indicated that even an inactive state may feature breakage of this lock.

In the GPCR jungle, strange shape-shifting creatures appear and clutch gems of insight in their palms. It is only fitting that we throw the kitchen sink at them to unravel their secrets, and computational techniques can only be a valuable arrow in this quiver.

Yarnitzky T, Levit A, & Niv MY (2010). Homology modeling of G-protein-coupled receptors with X-ray structures on the rise. Current opinion in drug discovery & development, 13 (3), 317-25 PMID: 20443165

Lindau 2010: Island Full of Ideas

noreply@blogger.com (Wavefunction) — Thu, 01 Jul 2010 18:39:00 +0000

I am very fortunate in being invited again to blog for the 60th Meeting of Nobel Laureates in Lindau, Germany. This year's interdisciplinary star-cast features more than 60 Nobel Prize winners from physics, chemistry and medicine and more than 600 young students and researchers from around the world. It's been a pleasure blogging for this one-of-a-kind meeting. Below are listed some of my posts with excerpts. You can click on the titles to read the full posts.

1. Reflections on Nobel City

Cities, just like human beings, have character. The character is frequently defined by little things as well as big. For instance New York is The Big Apple, Paris the city of fashion, Sydney the city with the Opera House and Rio de Janeiro the carnival city. Small cities are also known for their own accomplishments. For instance, last year I visited the the little German city of Magdeburg which is known for Otto von Guericke, the man who established the physics of vacuums through a famous experiment involving horses...

2. Microwaves, Magnetism and Machine Grease: A Paean to Tool-Driven Science

John Turton Randall was trying hard, real hard. For some time now, the University of Birmingham physicist was focusing on trying to improve the features of a machine which transmitted and received electromagnetic waves. A few years back this would have been just another intriguing academic problem for a physicist to crack, but this time it was a matter of life and death for thousands. Literally. It was 1939, and an ominous menace loomed large over Europe in the person of Adolf Hitler. The machine Randall was working on was designed to thwart Hitler's attempts to invade the British mainland. It sent out electromagnetic waves of meter wavelength and tried to deduce the position of an object based on its reflection of these waves. The operating principle of this humble machine later turned into a household name- Radar...

3. Pigeon Waste, Cosmic Melodies and Noise in Scientific Communication

There it was, that darned noise again.

Nobody could possibly be happy cleaning pigeon droppings. Yet Arno Penzias and Robert Wilson were being forced to do it. As good scientists they simply could not avoid it, since they had to discount the role of this "white dielectric substance" in the noise that was plaguing their equipment. When they finished with the cleaning and dispatched the pigeons by mail to a faraway place, the noise still did not disappear. And it seemed to come from all directions. The implications of this annoying constant background hum, corresponding to a temperature of only 3 degrees above absolute zero, signified one of the most momentous discoveries in twentieth-century physics, notable even among Nobel Prize-winning discoveries...

4. Paul Crutzen's Other Big Idea

Nobel Laureate Paul Crutzen will be at Lindau this year, along with his fellow recipient F. Sherwood Rowland. The two along with Mario Molina contributed to one of the most significant intersections of science with politics and public policy in the twentieth century when they discovered the effects of chlorofluorocarbons and other chemical compounds on the all-important ozone layer. Crutzen is well-known for that contribution...

5. Mountains Beyond Mountains

The scientist, by the very nature of his commitment, creates more and more questions, never fewer. Indeed, the measure of our intellectual maturity is our capacity to feel less and less satisfied with our answers to better problems.- G.W. Allport, Becoming, 1955

Science in the popular mind consists of a series of "Eureka!" moments. Such moments are supposed to suddenly propel scientific fields ahead at accelerating rates. Many anecdotes from scientific history seem to confirm this belief. It all begins with Archimedes jumping out of the bath after discovering the principle of buoyancy. Other examples include the apple falling on Isaac Newton’s head, August Kekule waking up from a dream and realizing the structure of benzene, Enrico Fermi discovering slow neutrons by ‘randomly’ substituting a block of paraffin for a tabletop, Alexander Fleming ‘accidentally’ discovering the action of a famous mold on bacteria, and Werner Heisenberg discovering the awesome structure of the quantum world after an all-night session on the island of Heligoland in the North Sea...

6. Heisenberg and Dirac

Beatrice's story about Heisenberg possibly inspiring the "Schunkelwalzer" dancing tradition at Lindau reminds me of an ancedote about Heisenberg and Paul Dirac. Both were two of the most accomplished scientists of the twentieth century who made foundational contributions to quantum mechanics. But while Heisenberg loved song, dance and wine, Dirac was a very quiet man and a singularly unusual character who generously extended his abstract thinking to interpreting the world literally. This inevitably led him to being an anecdote generator throughout his life and many stories about him abound. Here are a few, concluding with the story about him and Heisenberg...

7. Infections and Disease: The Golden Age

Harald zur Hausen's discovery of the link between infection and cancer provides a window into what may turn out to be one of the most fascinating lines of inquiry in twenty-first century medical research: the link between microorganisms and what have been traditionally considered chronic diseases.

This line of inquiry is founded on an evolutionary truth. Bacteria and viruses have been human beings' most constant companions, existing on this planet billions of years before we did and greeting us as we climbed out of the trees and walked out of Africa. Since the very beginning we have been engaged in an arms race with microbes. The conventional wisdom is that these arms races have led to an essentially benign co-existence between us and "them". But recent thinking has challenged this widespread belief and the truth appears to be more complicated...

Parallel worlds, parallel lives

noreply@blogger.com (Wavefunction) — Sat, 26 Jun 2010 00:22:00 +0000

"Parallel Worlds, Parallel Lives" is a documentary about Hugh Everett, the fascinating, brilliant and troubled physicist who conceived the idea of parallel universes, which have become a staple of science fiction ever since and are now being taken seriously even by serious scientists.

Everett received his PhD. from Princeton in the 1950s with John Wheeler. At the time the prevailing view of what happens when you observe a quantum system was the Copenhagen Interpretation which said that until you observe a quantum system it exists in a superposition of states; the wavefunction of such a system suddenly "collapses" when you observe it. This of course led to several dilemmas and paradoxes, the most famous one being Schrodinger's Cat. Several questions arose; when exactly does the wavefunction collapse? Who can collapse it? Everett bypassed the whole problem by assuming that quantum systems simply exist in many different states but in separate universes and you observe one of them. Thus the wavefunction does not collapse at all. This of course sounded fantastic, implying that at every moment, there is a copy of you for instance that splits into infinitely many copies in infinitely many universes. However, it did seem to provide a simple way out of Schrodinger's cat-type problems. The "many-worlds interpretation" of quantum mechanics has fascinated, troubled and interested scientists and laymen alike ever since.

Unfortunately, Bohr's "gospel" prevailed among physicists, and Bohr strongly disagreed with Everett in a meeting that Wheeler had set up between them. Disappointed and with a family history of depression, Everett left academia for good. He spent the rest of his life doing top-secret work for the government, coming up with algorithms and computer programs for modeling nuclear war. He apparently was very influential in suggesting nuclear weapons policy which the government adopted and several of his reports are still highly classified. One of the concepts he pioneered was the Lagrange multipliers method, a key tool in solving differential equations with constraints in diverse disciplines. He died suddenly of a heart attack in the 1970s. Everett had a drinking problem and a tragic family life. He was very distant from his children. His son who is the main subject in the documentary says that the only time he touched his father physically was after he died and the dead body had to be moved. Everett's daughter committed suicide, writing a bizarre suicide note saying that she was going to meet her father in a parallel universe.

The documentary is a NOVA documentary on PBS. It's about Everett's son, the musician Mark Everett (who seems to be quite successful with his band "The Eels") who sets out on a journey to Princeton, the Pentagon, Austin, Cambridge etc. to find out more about his father and speaks to such people as Charles Misner and David Deutsch. On the way he learns some quantum mechanics and gets to know his father much better. In the end he feels much closer to his father and seems to have finally received closure. It was rather touching to be honest and there is a sense of satisfaction in his son finally seeming to be at peace.

Note: A rather expensive biography of Everett has just come out. A cheaper, free version is a short Scientific American piece on him.

The origin of life cannot escape basic organic chemistry

noreply@blogger.com (Wavefunction) — Mon, 14 Jun 2010 21:11:00 +0000

One of the key challenges facing any theories of the molecular origins of life concerns the synthesis, stability polymerization and self-assembly of early life's molecular components. If you cannot explain the chemical origin of these components, you cannot really explain the origin of life. In case of life as we know it, this boils down to explaining the origin of the building blocks of living organisms, namely nucleotides and amino acids.

The simplest principles and quirks of chemistry could have had an influence on how life could have evolved. A neat paper in ACS Chemical Biology offers a potential explanation based on basic organic chemistry for why a certain class of phosphorylated nucleotides formed in preference to others, even though 'conventional' organic chemistry would dictate the opposite.

An anhydroarabinonucleoside has been postulated as an important potential precursor to further nucleotide synthesis. A key step is the phosphorylation of this nucleoside to yield an activated cyclic nucleoside phosphate. Having an activated molecule makes all the difference since activation primes the molecule to be attacked by further nucleophiles, thus triggering polymerization and growth.

However, the phosphorylation of the arabinose nucleoside raises a fundamental question (hopefully) familiar to sophomore organic chemistry students. Why does phosphorylation take place preferentially on the secondary 3'-OH while sterically, as every student of organic chemistry knows, it should be preferred much more on the primary 5'-OH?

To tackle this question, the authors get a crystal structure of the nucleoside in question. This x-ray structure shows an unusually short distance between the 2'-OH oxygen and the C2 carbon (2.7 A, a).

Energy optimization using quantum chemical techniques surprisingly does not get rid of the short distance. Because of this proximity, the 2'-OH can undergo an internal attack on this carbon to generate a reactive intermediate (1), whose ring can be opened in turn by a 3'-OH phosphate to form the activated phosphate product. Now, the 5'-OH also gets phosphorylated; it's just that it cannot attack the C3 carbon of the activated intermediate the way the 2'-OH can because it's not in proximity to this carbon the way the 2'-OH is.

The authors explain the short distance between the 2'-OH and the C3 carbon by postulating an interaction between the lone pair of the 2'-OH oxygen and the pi* orbital of the C2=N bond. This kind of interaction is quite familiar to organic chemists; it is invoked in the famous Burgi-Dunitz trajectory that enables nucleophilic attack on carbonyl carbons. Indeed, the authors perform a theoretical analysis that shows the angle of attack for the 2'-OH to be about a 100 degrees, close enough to the Burgi-Dunitz trajectory.

This is a classic case of there being two competing pathways in chemistry, one of which is preferred to the other because of a subsequent low-energy route that can be traversed. It's a common theme in chemistry and biochemistry and illustrates how otherwise counter-intuitive reactions can be accelerated by putting them at the top of the right energy cliffs. No matter how complex life may be, it still cannot get around the basic laws of organic chemistry. Score one for thermodynamics.

Choudhary, A., Kamer, K., Powner, M., Sutherland, J., & Raines, R. (2010). A Stereoelectronic Effect in Prebiotic Nucleotide Synthesis ACS Chemical Biology DOI: 10.1021/cb100093g

The aesthete

noreply@blogger.com (Wavefunction) — Thu, 10 Jun 2010 02:22:00 +0000

I had a great time visiting Santa Fe and Los Alamos over the weekend. At Los Alamos there is a nice little museum in Fuller Lodge, where the Manhattan Project scientists used to socialize on weekends. One of the amusing artifacts there is a set of two letters sent by Oppenheimer's secretary asking for a nail to be driven into the wall so that he could hang his hat. There is the first letter...and then there is the follow up.

It's remarkable that this intellectual aesthete did not have the practical drive to hammer a nail into the wall. One could not have imagined someone like Fermi or Feynman leaving the problem unattended for so long. In light of this it seems even more astonishing that a dyed-in-the-wool hands-off theoretician like Oppenheimer could not only direct a world-class group of Nobel Prize winning scientists and engineers to achieve the impossible in record time, but also keep the most practical details of an unimaginably vast project in his head. He even knew who was the best person in the country to manage the organic chemistry stockroom.

Physicist Victor Weisskopf of MIT said it well:

"He did not direct from the head office. He was intellectually and even physically present at each decisive step. He was present in the laboratory or in the seminar rooms, when a new effect was measured, when a new idea was conceived. It was not that he contributed so many ideas or suggestions; he did so sometimes, but his main influence came from something else. It was his continuous and intense presence, which produced a sense of direct participation in all of us; it created that unique atmosphere of enthusiasm and challenge that pervaded the place throughout its time"

Conformations of the stevastelins: A reassessment

noreply@blogger.com (Wavefunction) — Tue, 01 Jun 2010 18:10:00 +0000

Shameless self-promotion: my paper on the conformational analysis of cyclic antiviral peptides called stevastelins is now online on the Biopolymers site. Here's a brief overview.

The stevastelins are cyclic peptides that show promising antiviral activity against the vaccinia viral VHR phosphatase. These peptides are phosphorylated in vivo before they can inhibit their target protein. A group in Germany previously did a meticulous analysis of four diastereometric analogs of these peptides which included their synthesis, biological characterization and conformational analysis. However, the conformational analysis was done using force field conformational searches from a single force field, constrained by variables from the NMR data (coupling constant derived dihedral angles and NOESY derived distances). Using such a protocol, the group concluded that each of the four diastereomers exists as a single conformational family in solution.

The problem with constrained conformational searches (or constrained molecular dynamics for that matter) is that they constitute a rather self-fulfilling exercise, with the assumption that there is in fact a single conformation of the molecule under question. However, as I have often discussed on this blog, any molecule with a couple of rotatable bonds is going to exist as multiple conformers in solution, so an assumption of a single conformation would be fuzzy unless supported by more data. NMR by itself is of scant value in determining these conformations for thermodynamic and kinetic reasons. Plus, analyzing conformations using a single force field can be fraught with ambiguity, since every force field comes with its own set of parameters and convergence criteria. Especially trusting energies from force fields can be dangerous. In this case, the stevastelin peptides have 9 rotatable bonds each, so I thought it worthwhile to apply our previously developed and applied NAMFIS (NMR Analysis of Molecular Flexibility In Solution) methodology combining NMR variables with structures from extensive conformational searches to the enumeration of the conformational behavior of these interesting molecules.

The paper essentially describes the conformational variability obtained for each of the diastereomers. Many of the conformations are very similar to the previously postulated families, but some are quite different. There are also some striking observations that are corroborated; for instance, the use of a d-serine truly seems to 'lock' the peptides in a single conformation. Such a lock could be effected to counter the entropic penalty that a multiconformational ensemble of molecules might have to pay. The instructive general observation is that subtle changes in sterechemistry at one or two chiral centers can dramatically affect conformational behavior, a fact that continues to surprise and confound medicinal chemists. I also note that if the NMR data for the phosphorylated peptides were available, an interesting comparison of the conformational pool for the phosphorylated and unphosphorylated counterparts could be attempted. This would shed light on whether phosphorylation leads to less conformational variability or simply increases the proportion of a chosen subset of conformations of the peptides.

Comments, criticism and general feelings of chagrin are welcomed.

Jogalekar, A. (2010). Conformations of stevastelin C3 analogs: Computational deconvolution of NMR data reveals conformational heterogeneity and novel motifs Biopolymers DOI: 10.1002/bip.21504