Lindau: The teachings of the savants

Marie Curie once said that "Science is about things, and not people". While this statement is true and profound, the fruits of science are unmistakably linked to their human origins, postmodernist relativism notwithstanding. The scientists who make discoveries are human beings, and they shoulder their share of foibles and successes, petty rivalries and forthcoming generosity, despair and triumph. Their life displays cycles that any young researcher will go through in his or her future career...

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Lindau: Who is the joke going to be on?

When the controversial and talented physicist Edward Teller was doing a PhD. with the great Werner Heisenberg at the University of Leipzig, the question asked at the end of every group meeting that focused on a complex sequence of problems was "Wo ist der Witz?", supposed to be translated as "What is the point"? but more correctly translated as "What is the joke?". The joke part of it consisted of turning a wry eye at the world, donning the hat of the court jester who laughs even as the fire that he predicted would engulf the world rages on. The question about global warming that we ask is also "Wo ist der Witz"? and we only hope that the joke is not upon us and we can actually still get the last laugh. Whether we might was the topic of discussion of a panel on global warming on the final day of the 59th Meeting of Nobel Laureates at Lindau...

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Lindau: From fullerenes to global education

When I visit my favourite restaurant for lunch or dinner, I usually order a legitimate food item from the main course. But once in a while, just to indulge, I order a sample platter of appetizers. The appetizers don't always provide the deep satisfaction that I get from eating a proper, expensive food item. But they provide me with a different kind of unique satisfaction; they give me a glimpse of what's new, what's possible. They provide a view of the diversity that can emerge in a plate of bite-sized chunks. And through their frequent novelty, they give me hope that there are new possibilities on the horizon. These appetizers constitute occasional but necessary fodder. Sir Harold Kroto's talk was one of the most satisfying platter of appetizers I have sampled, and I had not even ordered it...
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Lindau: The way dinner should be

When you first meet Aaron Ciechanover, he appears to have the distracted air of a man who feels slightly inconvenienced to be in whatever situation has been apparently imposed on him. But this preoccupied demeanor belies a mind which is ready to hold forth on a disparate variety of topics with infinite verve and enthusiasm and which is not reluctant to be politically incorrect, provocative and utterly honest. And it hides a broad smile which is very readily revealed at the mention of a favourite incident or fact.

If there is one word to describe the Israeli doctor, biochemist and Nobel Laureate it's passion, and this passion is pronounced no matter what the topic of discussion; from protein degradation to languages and traveling, from politics to history. Whether we were talking about protein structure or Israel-Palestine relations, Ciechanover's thoughts were always opinionated, honest, cogent, provocative and without a dull shade in them. This is the kind of stimulating person that you always want as a dinner companion...

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Lindau: the glowing joy of discovery

Last year's chemistry Nobel Prize was one of the most softball predictions ever made for the Nobel Prize. The Green Fluorescent Protein (GFP) has become so widely used in chemistry, biology and medicine that it is easy to forget that someone had to discover it and develop the technology. Every year Roger Tsien's name used to be on everybody's favorite candidate list along with Martin Chalfie's and Osamu Shimomura's. Then last year, he along with Shimomura and Chalfie finally put the tortuous process and spilling of ink to rest.

A post about GFP is a writer's dream for indulging in pretty pictures. I will restrict myself to two. GFP has become a poster boy for the science of biotechnology. Its barrel shaped ß-sheet structure shown above has become iconic in the scientific world. This is most emblematic in the odd and many varieties of glowing animals that now grace the covers of everything from scientific journals to websites and children's textbooks. If as some have predicted, we happen to "domesticate" biotechnology in the next few decades, it is very likely that one of the first things that our children would do would be to produce glowing pet rabbits, dogs, mice and cats. Along with a few other icons like DNA and the fruit fly, the image of glowing animals and fluorescent proteins is now deeply ensconced in our imagination as an example of what humans can do by manipulating biological systems. Perhaps one day our children can become friends with transgenic, green, glowing human beings, without the hulk-like physique and temper tantrums...

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Wine, wisdom and wish-fulfillment at Lindau

This cannot get any better. There's everything here; the opportunity to interact with dozens of Nobel prizewinners in a very informal setting, spectacular views of the alps bordered by three countries (Germany, Switzerland and Austria), nice bicycle rides, a charming hotel to stay in, polonaises to dance to, great banquets with varied food and drink and a festive atmosphere, really nice people to interact with (my co-bloggers are super-friendly and helpful) and dinner with small groups of students and Nobel laureates. I could not have asked for anything more. Here's me with my wunderbar fellow bloggers. I also ran into Bora and PZ Myers and had a nice walk with them around town. Both of them are attending and vigorously blogging as usual and Bora was also part of a panel discussion on open science access.



This year India is a partner country and has sent the third-largest delegation of students, about 43. Guests included the minister for human resources Kapil Sibal and the minister for science and technology S. E. Chavan. As a partner country India hosted a wonderful banquet yesterday with lots of Indian food, followed by an Indian dance performance. This was followed by a Lindau tradition; a polonaise in which the ladies and the gentlemen form lines and ascend the stage from both sides. The gentlemen pick up a flower and present it to whichever lady happens to be in front of them in the center of the stage. The polonaise then breaks into a waltz, and the dancing continues late into the night. There is purportedly ghastly photographic evidence of a certain individual trying to waltz.

Most importantly, you cannot help but be taken in by the picture of hundreds of students from every possible country interacting so enthusiastically with each other, underscoring the global nature and brotherhood of science. Indians interact with Belorussians, Americans interact with Poles, Chinese interact with Russians, Zambians interact with Germans. And Nobel Prize winners participate in the dances and interact with everyone else. The atmosphere is truly international and sparkles with verve.

Today I had the opportunity to conduct an informal interview with Prof. Peter Agre whom I had also met last year. But this year it was one-on-one for 40 mins and was truly enjoyable since Prof. Agre is an exceptionally witty and nice person. You can read about the interview here.You can find the rest at the official Lindau blog, including all my posts (my name is right below each). Updating will continue all week long. Keep watching that spot for more!

Blogging from ground zero: day zero

I have finally arrived in Lindau, Bavaria to offer my thoughts on the meeting of minds between 500 students, 23 Nobel Prize winners in chemistry and the handful of acting scientific journalists such as myself. The journey itself was uneventful but very long. It took me almost the same time to get from Frankfurt to this little island as it took me to get from New York City to Frankfurt. I had to change trains twice, first at Mannheim and then at Stuttgart. Plus I think I am still to savor the punctuality of German transport since my train was delayed by more than half an hour at Stuttgart and then twice more at miscellaneous stops. However I have to admit that this still beats driving or any form of personal transport.

I cannot yet offer my thoughts on the environment Lindau provides, but one thing stuck out as I passed over a bridge; a spectacular view of the Alps on the other side of the Bodensee. Again, I have yet to see around, but an island at the base of the alps which is located in Germany, Austria and Switzerland cannot exactly be dull and ugly, can it?

I have already started blogging on the Lindau blog website and I would prefer not to cross-post that material in other places. Here is the link to the website and to my first three posts:

Lindau blogs website

Exemplifying apprenticeship; The Lindau meetings

Diversity of talks; diversity of science

Surfaces, ammonia, ozone and scientific destiny

Live-blogging starts tomorrow! Here is the program for tomorrow:

"The partisans have ampicillin". Really?

The Russian covert antibiotic program must have been hugely successful



In an effort to stave off the boredom that inevitably accompanies adjustment to a new environment, I was watching the WW2-era movie "Defiance" yesterday. The movie is based on an astounding true story about two Jewish brothers (played by Daniel Craig and Liev Schreiber) who hide and lead a band of Jewish refugees through the forests of Belorussia for two years and thwart the Nazis' plans for their extermination. Surviving on food killed and obtained in the jungle, defending themselves with stolen small firearms and occasionally seeking the help of partisans from the Red Army, the Bielski brothers and their group provide one of the most exemplary stories of resistance against the Nazis during the war.

So far so good, and the movie is not bad at all. But during one scene my ears suddenly perked up. There is a winter epidemic of typhus threatening to wipe out the population. A nurse tells Craig that the disease is spread by lice and without medical attention the patients will certainly die. To prevent this, she says, Craig and his group must borrow ampicillin from the Red Army. "The partisans have ampicillin", she says with hope and concern.

Which is all fine, except that ampicillin was not even known in 1942. It was introduced only in 1961. Even penicillin was a closely guarded secret in 1942. Plus I am not even sure if typhus is properly treated with beta-lactam antibiotics.

I was further chagrined when in order to confirm this I visited the Wikipedia page on penicillin. While it otherwise looked ok, it also said that the first total synthesis of penicillin was achieved by Woodward. Again, not true. Woodward synthesized cephalosporin. It was John Sheehan from MIT, a mentor of E J Corey, who synthesized penicillin after a mammoth effort of 15 years. The error is now rectified.

Seems the directors of Defiance and the editors of the Wikipedia penicillin page have the same problem of fact-checking.

So what exactly are force fields good for?

Sue Storm tries hard to use her favorite force field to counter the 1 kcal/mol barrier



Every once in a while there is a study asking what method X (X = docking, free energy calculations, molecular dynamics, force fields etc.) is good for. Such studies can be useful to take stock of a particular paradigm. So the question that Jonathan Goodman and his group ask in this paper is "Are force fields good for reproducing non-bonded interactions, especially hydrogen bonding, pi-stacking and dispersion?". He and his group compare very high-level quantum chemical ab initio data with data obtained from the most commonly used force fields, namely MM2*, MM3*, MMFFs, OPLS-2005 etc. The ab initio data used is from Pavel Hobza who has almost consummately published on these methods. The question is; how well do the force fields do compared to the gold standard? The answer is necessarily incomplete and complex and again raises many interesting questions about the enigmatic role of hydrogen bonding in chemical and biological systems.

The complexes studied include purely pi-stacked complexes, purely hydrogen bonded complexes and mixed complexes where both interactions play roles. Typical examples include alcohol-amide complexes, water oligomers and of course, the classic stacked and hydrogen bonded DNA nucleoside bases. The parameters that the authors looked at were geometries and energies, both of optimized complexes as well as crystal structures.

The results are perhaps not too surprising; the more recent OPLS-2005 and MMFFs are probably the best in reproducing known geometries and energies while MM2* and MM3* don't perform that well in general. As noted in some other studies, at least some of the results for MMFFs and OPLS compare with those obtained with high-level ab initio calculations, thus indicating the value of these cost-effective methods for geometry optimization and energy determination (let's ignore for a moment that solvation models in ab initio methods make even these less than perfect).

What is more important though is that all the force fields are generally not good for reproducing hydrogen bonded systems compared to systems where dispersion, stacking etc. are the key players. This is partly an indication of the tricky events including long-range solvation which play an important role in h-bond formation. But what is interesting is that the methods underestimate the energetics of hydrogen bonds. While I am a little puzzled by this, one of the explanations that comes to my mind regarding this curious fact is that in real systems, h-bonding is a cooperative interaction. An h-bond can pay for loss of entropy, thus making the overall free energy of the next h-bond more favourable. Of course force fields don't calculate free energy, but to a first approximation we can probably assume that the enthalpy and free energy are similar for these simple systems. To be honest, because of the complex nature of long-range dispersion interactions I would have assumed that the force fields would be worse in modeling these. I frankly don't understand why they work better for such interactions but it's an interesting observation.

But now for some general thoughts; it's always worth remembering that for molecules like proteins which are stabilized by h-bonds, the h-bonds when formed are simply swapped for similar bonds with water, thus making a relatively insubstantial contribution to protein stability. It is the large number of such interactions that can tip the balance for a protein, but the real driving force is now universally recognized as the hydrophobic effect and the burial of non-polar groups. Calculations such as those above indicate that because of the fine-tuning of h-bonds that proteins often use to achieve stability, force fields have some way to go in predicting tiny energy differences. It is still a great challenge to model the sub-angstrom geometry optimization of h-bonds that biopolymers achieve. But force fields are hardly unique in not being able to do this; so are other methods which are still trying to break the 1 kcal/mol barrier. Ironically in this study, the mean unsigned error when the hydrogen-bonded complexes are included is about 1 kcal/mol.

So are force fields good for anything at all? The short answer is yes, exemplified by the massive number of publications that regularly use force fields as well as the substantial number of people in academia and industry studying them. Obviously people think they are important, otherwise so many common programs doing everything from protein folding to drug-protein interactions would not have relied on them. I have had reasonable experience with force fields and have always kept in mind a couple of things about them that are worth reiterating:

1. Force fields are usually good at reproducing geometries, and best for reproducing sterics.
2. Force fields are usually not so good at reproducing energies since energy estimation is a function of the special parameterization and convergence criteria unique to every force field (As the Zen master says, "What the answer is depends on what question you ask"). However, relative conformational energies using a single force field for instance may be useful.
3. As a corollary, force fields can be pretty poor for dealing with molecules having a large number of polar functional groups. While this means that peptides are hard to model, modeling of peptides has also been mitigated by the fact that unlike small molecules, the chemistry to be parameterized is limited.
3. Many times the real problem is not with force fields per se but with the accompanying implicit solvation models. Admirable effort has been expended in developing these models but to be honest we still don't understand enough about that enigmatic solvent named water to do a satisfactory job. We are just scratching the surface when it comes to modeling things like solvent entropy for instance.

If you are following the field's developments, you also see an engaging and ongoing debate that pits the "science first" camp against the "parameterization first" camp. The science first camp disapproves of the other camp's efforts to improve their force fields simply by adding more parameters and optimizing against experiment; to them it is much more important to meticulously improve the methodology by incorporating as much real science as possible. The parameterization first camp argues that statistical methods have their honored place in the annals of science and that getting results fast and efficiently is important for application-oriented scientists like drug discovery people. I believe that as in other matters, both sides are right. It is an uncomfortable feeling when you don't truly understand the science behind a method and yet the method works, but at the same time it is important to have a well-parameterized and tested model that could help you in a practical sense, even if incompletely understood.

As with everything else, finally it is an astute application of force fields that takes into account their strengths and limitations which will lead to productive results. One of the most interesting things about doing science involves weighing the pros and cons of methods, techniques and algorithms and deciding what judicious combination would provide the best answer and why. It may not always work, but it could keep us from getting seduced by the dark side of the force (field)

Paton, R., & Goodman, J. (2009). Hydrogen Bonding and π-Stacking: How Reliable are Force Fields? A Critical Evaluation of Force Field Descriptions of Nonbonded Interactions Journal of Chemical Information and Modeling, 49 (4), 944-955 DOI: 10.1021/ci900009f