TITLE: Computational Solvent Mapping of Proteins

SPEAKER: Professor Sandor Vajda

TIME: Tuesday Jan. 21, 2003 at 3 PM

PLACE: George P. Williams, Jr. Lecture Hall, (Olin 101)

Enzyme structures determined in organic solvents show that the small ligands bind only at a few positions, and primarily at the active site. We have developed a mapping algorithm that moves molecular probes - small molecules or functional groups - on a protein surface to find the regions with favorable binding free energy. Results will be presented for a number of proteins which have been mapped experimentally or have a well characterized binding site. In good agreement with experimental data, the mapping algorithm finds the consensus site at which different solvent molecules bind, eliminating the problem of spurious local minima associated with previous computational methods. A very important result is that using at least six different solvent as probes, the consensus sites found by the mapping are always in the major subsites of the functional site, and as a result, the amino acid residues that interact with the probes also bind the specific substrates of the enzyme. Thus, computational mapping provides detailed and reliable information on the functional sites of proteins. The mapping also shows that the consensus site accommodates each ligand in a number of rotational states, resulting in favorable entropic contributions. Applications of mapping to problems in structural genomics, enzymology, and drug design will be discussed.