Automated Molecular Structure

A team of researchers led by Nobel prize-winning biophysicist Herbert Hauptman appears to have cracked one of the premier problems in contemporary science -- the phase problem of x-ray crystallography. Using massively parallel computing at the results that cut the time required to determine the structure of molecules that now take months and years to hours.

By throwing the bulk of the process onto a supercomputer, the Shake-and-Bake numerical recipe offers an almost automatic path to solving unknown structures for medium-sized molecules. Structures in this range include small proteins and many antibiotics. "The central importance of this," says Hauptman, "is that it would enable us to design more effective drugs, either for the prevention or treatment of disease, and to do it in a rational, intelligent way, rather than by trial-and-error."

Shake-and-Bake is now implemented as a production tool on the CRAY T3D at Pittsburgh Supercomputing Center, and the PSC biomedical program offers training on how to use it.


Two Protein Structures determined by Shake-and-Bake

The unit cell molecular structure of gramicidin A (left) and ternatin (right) as determined by Shake-and-Bake. Gramicidin A is an antibiotic composed of 317 atoms. It acts as a membrane pore in cells, which is why the structure forms a tube along its central axis. To determine this structure originally (accomplished by David Langs of the Medical Foundation of Buffalo) required about 10 years using traditional direct methods. With Shake-and-Bake it took several months. Semi-transparent spheres represent atoms and the short lines represent possible chemical bonds. To arrive at a final, refined structure, the Shake-and-Bake solution is fed into a crystallographic refinement program.

Ternatin is a 110-atom compound similar to cyclosporin, the immune system suppressant used in transplant surgery. This structure was unknown untill Shake-and-Bake came up with the solution in July 1992, the first time the program solved a previously unknown structure. Russian scientists had worked for years without success on this structure.

Researchers: Herbert A. Hauptman, Medical Foundation of Buffalo; Russ Miller,SUNY at Buffalo.
Hardware: Connection Machine CM-2 and CM-5, CRAY T3D
Software: Shake-and-Bake
Keywords: molecule, molecular biology, molecular structure, x-ray crystallography, phase problem, parallel solution, direct method, Shake-and-Bake, algorithm, protein, ternatin, gramicidin, antibiotic.

Related Material on the Web:
Shake-and-Bake Home Page, citations to technical articles, FAQs and more.
Projects in Scientific Computing, PSC's annual research report.

References, Acknowledgements & Credits