PREDICTION OF PROTEIN COMPLEXES USING EMPIRICAL FREE-ENERGY FUNCTIONS

A long sought goal in the physical chemistry of macromolecular structu re, and one directly relevant to understanding the molecular basis of biological recognition, is predicting the geometry of bimolecular comp lexes from the geometries of their free monomers. Even when the monome rs remain relatively unchanged by complex formation, prediction has be en difficult because the free energies of alternative conformations of the complex have been difficult to evaluate quickly and accurately. T his has forced the use of incomplete target functions, which typically do no better than to provide tens of possible complexes with no way o f choosing between them. Here we present a general framework for empir ical free energy evaluation and report calculations, based on a relati vely complete and easily executable free energy function, that indicat e that the structures of complexes can be predicted accurately from th e structures of monomers, including close sequence homologues. The cal culations also suggest that the binding free energies themselves may b e predicted with reasonable accuracy. The method is compared to an alt ernative formulation that has also been applied recently to the same d ata set. Both approaches promise to open new opportunities in macromol ecular design and specificity modification.