Stimulating quasi-erotic excitement through organic structure determination

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

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...

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...

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

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

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

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.