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Dr. Sarel Fleishman. Designed to fit
Does the perfect match exist? Despite the promises of numerous dating sites, finding the ideal mate is rarely a rational, systematic process. Until now, the same could be said for matches between protein molecules. We might be able to observe which proteins get together – which pairings initiate molecular processes and which block them – but we haven’t really been able to generate novel, “perfect” matches from scratch.

This situation is now changing, however, thanks to a new method, the first of its kind, for “fine tuning”  various physical features on the surface of a protein molecule. The method, developed by Dr. Sarel Fleishman – who recently joined the Institute’s Biological Chemistry Department – and his colleagues at the University of Washington, Seattle, enables researchers to redesign the surface of protein molecules so that they will match up with target proteins and strongly bind to them.
For instance, the scientists created new proteins that can bind to the active site on the surface of a flu virus, obstructing its activities. This particular site has been conserved throughout the evolution of the flu, so it is found in many strains including bird and swine flu. Thus a protein molecule like the one Sarel and his colleagues programmed to target that site could conceivably block a range of flu viruses. The therapeutic potential of these molecules is currently being investigated.

In addition to sophisticated computer analyses of the physical properties of protein molecules, the system makes use of a number of online databases of protein molecule structures (including pioneering databases developed at the Weizmann Institute). According to Fleishman, the process begins with a theoretical computation to determine the ideal molecular structure needed to perfectly bind to the active site of a target protein. The next step is to scan the protein structure databases to find natural molecules into which the programmed active site might feasibly be integrated.
In the case of the new flu-binding protein, several dozen proteins were altered to include the new binding site. Of these, five succeeded in the lab in binding to the targets. One of the five managed to block the ability of various flu viruses to spread.
The molecular structure of Spanish flu protein (hemagglutin) bound to a computationally designed protein (green). The designed protein binds the viral protein tightly and with high specificity, blocking the protein's function and neutralizing viral infectivity
“Basically,” says Fleishman, “by combining our computational tools with an experimental approach, we were able to create molecules that don’t exist in nature. Such programmed molecules could give us the ability to direct molecular activities, and they might have a wide range of uses in medicine, diagnostic tools and biotechnology.” In other words, nearly ideal matches – ones that don’t exist in nature – can now be produced with a computer and a biology lab. The method might be used, in the future, to design a variety of new drugs, including those to combat emerging diseases for which current drugs may be ineffective.
Dr. Sarel-Jacob Fleishman’s research is supported by Sam Switzer and family; the Geffen Trust; and the Yeda-Sela Center for Basic Research.