Fit to Win: Weizmann Institute Scientists Win Biochemical "Docking" Contest

REHOVOT, Israel -- March 20, 1996 -- Imagine trying to put together a three-dimensional puzzle while blindfolded. Weizmann Institute scientists have just won an informal international contest for performing an equally challenging task -- predicting how two large, convoluted protein molecules would fit together in nature.

To make such predictions, researchers use "docking" algorithms, sophisticated computer programs enabling them to rotate three-dimensional representations of molecules at various angles and match them against one another to determine the most likely way in which these molecules will fit together.

Such algorithms are employed in the development of new drugs and various other chemicals, providing valuable insights into the nature of biological molecular complexes and helping scientists cut down on costly and time-consuming experiments in the lab.

In the contest, whose results are described in the March issue of Nature Structural Biology, "dockers" throughout the world had been asked to predict an unknown structure of a molecular complex. While the scientists got busy trying to make the predictions, the group of Prof. Michael N.G. James of the University of Alberta, Edmonton, Canada, which launched the contest, determined the structure of this complex experimentally, using a method known as X-ray crystallography.

Once the actual structure was described, it was matched against the 40 predictions submitted by six research groups worldwide. The purpose of the exercise was to test the efficacy of various "docking" algorithms.

One of the predictions submitted by Weizmann Institute scientists provided the closest match to the actual structure of the complex. It was based on an algorithm developed by a group of Institute scientists that brought together chemists and biologists specializing in protein structure with physicists specializing in pattern recognition for robotics and other nonbiological applications.

The group was headed by Institute Professor Ephraim Katchalski-Katzir, a noted pioneer in polymer chemistry, who also served as Israel's Fourth President from 1973 to 1978. The algorithm was used to produce the predictions by Dr. Miriam Eisenstein, who runs the Molecular Modelling Unit in the Institute's Chemical Services.

The object of the informal competition was the molecular complex formed when beta-lactamase, an enzyme that destroys penicillin-like antibiotics, binds with a protein that inhibits its function. Binding -- the joining of molecules in a lock-and-key fashion -- lies at the basis of all biological processes because it allows molecules to interact.

It occurs when compatible regions on the molecular surfaces recognize each other. Understanding of the binding between betalactamase and its inhibitor may lead to improved ways of preventing the enzyme from interfering with the beneficial action of antibiotics.

Apart from Dr. Eisenstein, Prof. Katchalski-Katzir,s group included Prof. Asher Friesem of the Department of Complex Systems, Dr. Isaac Shariv, Prof. Friesem's Ph.D. student at the time, Dr. Claude Aflalo, formerly of the Department of Biochemistry, and Dr. Ilya Vakser, formerly of the Dept. of Membrane Research and Biophysics.

Prof. Katchalski-Katzir holds the Theodore R. Racoosin Chair of Biophysics, and Prof. Friesem, the Peter and Carola Kleeman Chair of Optical Sciences.

Funding for this research was provided by the Raschi Foundation.

The structure of the beta-lactamase-inhibitor complex was determined and the predictions evaluated by Dr. Natalie Strynadka of the University of Alberta, Edmonton, Canada.

The Weizmann Institute of Science is a major center of scientific research and graduate study located in Rehovot, Israel.