Field of Science

SAMPLing out in the desert

I am in the absolutely charming Santa Fe, NM for the CUP IX OpenEye meeting. OpenEye's ROCS and related programs have become quite popular with the modeling and drug discovery community in the last couple of years. This year, as I had written about before, they have a challenge named SAMPL for all groups across the country involved in drug discovery modeling- provided with a few ligands and targets, do virtual screening, pose prediction and binding affinity prediction. It was a great opportunity for our small group of four grad students and postdocs to take part in the challenge.

The OpenEye meeting is always a spirited, extremely informal and funny meeting. The titles of talks makes it clear what kind of atmosphere enlivens the event. There are some really smart and interesting people here, heavily involved with all aspects of modeling and drug discovery. The Hotel La Posada, with its quaint spread-out low-lying adobe hut-like rooms adds to the charm.

The talks have been enlightening, and especially today's talks on crystallography and structure were very good. The most useful were those which focused on errors in crystal structures and crystallographic models- and there are a lot of them out there. The most terrific talk was by Gerhard Kleywegt from Uppsala. He talked about the myriad number of errors existing in crystal structures in the PDB, including misplaced ligands in little or no electron density (protein crystallographers can be especially negligent about ligand fitting, which unfortunately is of greatest interest to medicinal chemists), neglect of water molecules, incorrect conformations, and of course the rash of strained structures, poor resolutions and bad B-factors and R-factors. There are programs such as Afitt which can refine these structures. But a lot of people use crystal structures as they are and don't take account of such inadequacies. Some crystal structures are completely wrong, and yet exist in the PDB. Kleywegt's talk was very funny and informative, and gave a very good reason for why anyone who uses PDB crystal structures should be more than cautious in using them as they are.

Tomorrow there are some great talks on lead optimization and statistical techniques in methods evaluation. And Wednesday is going to be devoted to a brainstorming session on the SAMPL challenge. It would be very interesting to compare our own work with that of others. All in all, it is getting to be a refreshing scientific experience.

Otherwise the city of Santa Fe is very scenic and historical. Buildings have to be built to certain historical Spanish-Indian construction guidelines. And just a short walk from our hotel is 109 East Palace, which was the Manhattan Project's front office, where new arrivals were "inducted" and passes were issued to them so that they could travel to the secret city of Los Alamos, a place that did not exist on the map. Today the room is just a shop with no inkling of what went on there. Little do people strolling around know the great men that passed through those doors and walked that street- Oppenheimer, Fermi, Bethe, Teller, Frisch, Bohr...the list goes on.


  1. Waaait. Does "unrefined" mean what I think it does? As in, you just solve it and leave it as is? If so, that's kinda horrifying. Small-molecule people like to refine ours to death. I know we're not dealing with anything nearly as large as a protein, but still...!
    Damn you, lazy biologists!

  2. By "unrefined", I mean not going all the way through to make sure there's no funky stuff. You would expect that crystallographers would do the usual refinement, but beyond that too there could be serious problems. I don't know if it's a problem for small-molecule structures, but even there, one of the problems surely would be that you can place ligands in multiple ways in the ED, and some of the ways would not make chemical sense; consider the fact that one can often fit O and N equally well in the density. But then one of the points Kleywegt made was that more than occasionally, crystallographers are not very good chemists. So they don't understand things like strained conformation or unreasonable looking bond lengths or clashes. In the end, almost everything we use is a model, and a model is unfortunately a model is now what's "really" out there, hence the caveat.

  3. I almost started my neurology practice in Santa Fe back in '72, but someone else moved in first. My wife and I thought the place was charming, but it also appeared to be a 'toy town' with very rich people, very poor people and essentially no middle class. Is this still true ? A fascinating place to visit -- be sure to see the Taos Pueblo while you're there


  4. Interesting. I get the feeling it's still largely like that; certainly a lot of rich retired people here. Thanks for the recommendation. I am also planning on visiting Bandelier.


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