Hydrogen bonding and molecular surface shape complementarity as a basis for protein docking

A geometric docking algorithm based upon correlation analysis for quantification of geometric complementarity between protein molecular surfaces in close interfacial contact has been developed by a detailed optimization of the conformational search of the algorithm. In order to reduce the entire conformation space search required by the method a physico-chemical pre-filter of conformation space has been developed based upon the a priori assumption that two or more intermolecular hydrogen bonds are intrinsic to the mechanism of binding within protein complexes. Donor sites are defined spatially and directionally by the positions of explicitly calculated donor hydrogen atoms, and the vector space within a defined range about the donor atom-hydrogen atom bond vector. Acceptor sites are represented spatially and directionally by the van der Waals molecular surface points having normal vectors within a predefined range of vector space about the acceptor atom covalent bond vector(s). Geometric conditions necessary for the simultaneous hydrogen bonding interaction between both sites of functionally congruent hydrogen bonding site pairs, located on the individual proteins, are then tested on the basis of a transformation invariant parameterization of the site pair spatial and directional properties. Sterically acceptable conformations defined by interaction of functionally, spatially, and directionally compatable site pairs are then refined to a maximum contact of complementary contact surfaces using the simplex method for the angular search and correlation techniques for the translational search. The utility of the spatial and directional properties of hydrogen bonding donor and acceptor sites for the identification of candidate docking conformations is demonstrated by the reliable preliminary reduction of conformation space, the improved geometric ranking of the minimum RMS conformations of some complexes and the overall reduction of CPU time obtained. (C) 1996 Academic Press Limited