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 component is added to the energy and forces similarity between homologous proteins. Results: The combination was tested for two families: pancreatic hormones and homeodomains. The simulated lowest-energy structure of the pancreatic hormones is a reasonable approximation to the native fold. The lowest-energy structure of the homeodomains has 80% of the native contacts, but the helices are not packed correctly. The fourth lowest energy structure of the homeodomains has the correct helix packing (RMS 5.4 Å and 82% of the correct contacts). Optimizations of 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.