Chembark is back!

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

Briefly noted

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

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

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

"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

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

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

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?

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

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...