Field of Science

A first-class mental workout

Image Hosted by

I am back from the CUP X OpenEye conference in Santa Fe. Of all the conferences I go to, none is more intellectually stimulating, and very few have the same quality of food for thought. I have also not been to another conference where people grapple with such fundamental scientific problems; shape, electrostatics, statistics, dipole moments, force fields, tautomers. It's a treat for the brain, and it's just the shot of intellectual energy that I need to re-energize myself for doing and discussing science. Plus, I get to visit Santa Fe whose mountains can inspire even the most muddle-headed scientific thinker to come up with at least a few inspired ideas. As Linus Pauling said, first you need to have lots of ideas, then throw the bad ones away.

The cast of characters this year was delicious since they had invited keynote speakers from all nine previous CUPs back. You therefore got to hear about a smorgasbord of topics from folks like Barry Honig, Vijay Pande, Tack Kuntz, Ajay Jain, Paul Labute, Anthony Nicholls, Chris Bayly, Yvonne Martin and many more. The topics ranged all over the place, the humor flowed abundantly, but the focus was always on the basic science. In computational chemistry (or finance or physics or biology for that matter...) we build so many models, yet how many of them reflect true understanding of the underlying physical basis? Simply adding parameters can make a model fit the data, yet how many of us would be nonchalant about using it for new prediction? As von Neumann said, with enough parameters we can indeed fit elephants on a curve. Yet who knows if we would be able to fit all those wondrous creatures that currently exist only in our imagination?

Scientists at CUP X grappled with these issues with infinite concern and zeal. They asked questions like; Can we say we can predict if we can't even get the dipole moment right? Would force fields ever reach the golden standard? Can we predict which tautomer of a molecule will bind to a protein? Can we make quantitative calculations of thermodynamic quantities that we can compare to accurate quantities obtained from ITC data? How can we predict solvation energies? What biases do we have in modeling? Can we get rid of them? And then, how can we ensure only the most rigorous standards for the experimental data itself? As someone indicated, a PDB or CSD structure of a molecule that you see on a screen is not the data, it is only a model of the data. And finally, an eternal question; can quantum mechanics get us to heaven?

If you are any kind of chemist concerned about and connected with building models of chemical and biochemical reality, I would strongly urge you to attend the OpenEye conference, held every year in March in the Land of Enchantment. Registration is free, a few meals are provided, alcohol splashes around with abandon during the poster sessions, and the conference is usually in a nice downtown Santa Fe hotel (the elegant and spacious El Dorado in this case), deals for which are usually cheap if done early. I am going to be here, if possible, every single year that I can. Being here reminds me of a reviewer's assessment of Douglas Hofstadter's magnificent "Gödel, Escher, Bach": It is like having a first-class mental workout in one of the finest intellectual gyms around


  1. Good to see that Tack is still in the ball game. We were friends back in college. Back then, he was never happier than when working with large machines, and happiest when he could actually climb inside one (as I saw him do once).

    On a more serious note, what would you recommend to start reading about molecular dynamics? After auditing a PChem course, I'm polishing up my understanding of thermodynamics by reading the sections in Berry Rice and Ross 2nd Edition --a marvellous text which reads like a novel, but there doesn't seem to be anything about molecular dynamics in it. If you want to see how horribly dull PChem can be made to be, have a look at Glasstone which was a major text back then.

    As an outsider, I have great concerns about trusting molecular dynamics simulations (particularly as they involve protein folding) and wonder how much post hoc propter hoc is built in to them. From your report of the conference, it seems like the experts in the field do as well, at least when they let their hair down.


  2. Interesting to know that you were friends with Tack in college. He is indeed still in the game and is physically lean and mentally sharp as a well-tuned violin. He gave a beautiful talk on structure-based design and docking, a field which he founded. What was impressive to me is he could follow all the talks and asked questions at the end of almost every one.

    The Berry Ross and Rice book is indeed very good although I haven't been through all the chapters. It's interesting that you mention Glasstone. I had browsed through many of his book in college, especially the volumes on thermodynamics and electrochemistry. His PChem book is admittedly dull, but there are very few technical writers who are of the same caliber. Have you seen his "Sourcebook on Atomic Energy". It's one of the finest examples of technical writing I have seen, yet comprehensible to the general public.

    Regarding MD, there are many approaches. A prior course in stat mech definitely helps. If you want the fundamentals, I would recommend Allen and Tildesley's "Molecular Simulations of Liquids". If you want a basic treatise on application to biomolecules, then Andrew McCammon's book is good, if a little old. The chapters on MD in both Chris Cramer's and Andrew Leach's books on comp chem are pretty good. As an aside I would recommend Cramer as a generally excellent book; he knows his stuff really well and parts of the book are very well thought out and deep.

    There is also a review by McCammon which is informative:

    Molecular Dynamics: Survey of Methods for Simulating the Activity of Proteins
    Stewart A. Adcock and J. Andrew McCammon*
    Chem. Rev., 2006, 106 (5), pp 1589–1615
    Publication Date (Web): February 09, 2006 ()
    DOI: 10.1021/cr040426m

    Results from MD should indeed be treated carefully. Firstly you can never be sure you have sampled adequate conformational space in the context of your problem, so you might have missed the solution. Also, MD like other techniques suffers from the well-known problems with force fields that I have often mentioned here. These days I sometimes think of FFs as a battery inside electronic equipment. No matter how fancy your devices may be, they are not going to work well if the battery does not work well.

  3. Thanks for the references. Cramer is currently checked out of all the college libraries nearby -- a pretty good recommendation -- so I've ordered it.

    What do you think of [ Proc. Natl. Acad. Sci. vol. 106 pp. 3137 - 3141 '09 ] It concludes that the current value of the peptide solvation enthalpy is seriously wrong. Why is it wrong? Because it neglects electrostatic interaction with neighboring NHCO groups. They say that the solvation enthapy of the peptide bond depends on the context (e.g. neighboring NHCO groups) -- something intrinsically logical to an organic chemist.

    Since the solvation enthalpy is a basic parameter in analyzing the energetics of protein folding, their conclusion (if correct) should set the field on its ear. I know enough thermodynamics to follow the experimental work, but not enough to follow the DelPhi program and esf values. What's your opinion on all this?


  4. You should certainly find Cramer useful. While Leach is more diverse and also focuses on drug discovery-related topics like QSAR and docking, Cramer is more foundational and more pedagogically sound in my opinion (although it demands a little effort which is well rewarded).

    I will take a look at the paper you mentioned and get back to you; it certainly sounds interesting and Robert Baldwin is a man who knows his stuff eminently well. I have enjoyed reading some of his past articles. Especially check out:

    Robert L. Baldwin
    In Search of the Energetic Role of Peptide Hydrogen Bonds
    J. Biol. Chem., May 2003; 278: 17581 - 17588 ; doi:10.1074/jbc.X200009200


Markup Key:
- <b>bold</b> = bold
- <i>italic</i> = italic
- <a href="">FoS</a> = FoS