Protein docking and complementarity.
Predicting the structures of protein-protein complexes is a difficult problem owing to the topographical and thermodynamic complexity of these structures. Past efforts in this area have focussed on fitting the interacting proteins together using rigid body searches, usually with the conformations of the proteins as they occur in crystal structure complexes. Here we present work which uses a rigid body docking method to generate the structures of three known protein complexes, using both the bound and unbound conformations of the interacting molecules. In all cases we can regenerate the geometry of the crystal complexes to high accuracy. We also are able to find geometries that do not resemble the crystal structure but nevertheless are surprisingly reasonable both mechanistically and by some simple physical criteria. In contrast to previous work in this area, we find that simple methods for evaluating the complementarity at the protein-protein interface cannot distinguish between the configurations that resemble the crystal structure complex and those that do not. Methods that could not distinguish between such similar and dissimilar configurations include surface area burial, solvation free energy, packing and mechanism-based filtering. Evaluations of the total interaction energy and the electrostatic interaction energy of the complexes were somewhat better. Of the techniques that we tried, energy minimization distinguished most clearly between the "true" and "false" positives, though even here the energy differences were surprisingly small. We found the lowest total interaction energy from amongst all of the putative complexes generated by docking was always within 5 A root-mean-square of the crystallographic structure. There were, however, several putative complexes that were very dissimilar to the crystallographic structure but had energies that were close to that of the low energy structure. The magnitude of the error in energy calculations has not been established in macromolecular systems, and thus the reliability of the small differences in energy remains to be determined. The ability of this docking method to regenerate the crystallographic configurations of the interacting proteins using their unbound conformations suggests that it will be a useful tool in predicting the structures of unsolved complexes.
Shoichet
B K
BK
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143-0446.
Kuntz
I D
ID
D000465:Algorithms; D002918:Chymotrypsin / Q000737:chemistry; D003198:Computer Simulation; D010450:Endopeptidases / Q000737:chemistry; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*; D013381:Subtilisins / Q000737:chemistry
D011480:Protease Inhibitors; D011506:Proteins; D010450:Endopeptidases; D013381:Subtilisins; D002918:Chymotrypsin