SIMULTANEOUS AND COUPLED ENERGY OPTIMIZATION OF HOMOLOGOUS PROTEINS -A NEW TOOL FOR STRUCTURE PREDICTION

Background: Homology-based modeling and global optimization of energy are two complementary approaches to prediction of protein structures. A combination of the two approaches is proposed in which a novel compo nent is added to the energy and forces similarity between homologous p roteins. Results: The combination was tested for two families: pancrea tic hormones and homeodomains. The simulated lowest-energy structure o f the pancreatic hormones is a reasonable approximation to the native fold. The lowest-energy structure of the homeodomains has 80% of the n ative contacts, but the helices are not packed correctly. The fourth l owest energy structure of the homeodomains has the correct helix packi ng (RMS 5.4 Angstrom and 82% of the correct contacts). Optimizations o f a single protein of the family yield considerably worse structures. Conclusions: Use of coupled homologous proteins in the search for the native fold is more successful than the folding of a single protein in the family.