DOCKING ENZYME-INHIBITOR COMPLEXES USING A PREFERENCE-BASED FREE-ENERGY SURFACE

We present a docking scheme that utilizes both a surface complementari ty screen as well as an energetic criterion based on surface area buri al. Twenty rigid enzyme/inhibitor complexes with known coordinate sets are arbitrarily separated and reassembled to an average all-atom rms (root mean square) deviation of 1.0 Angstrom from the native complexes . Docking is accomplished by a hierarchical search of geometrically co mpatible triplets of surface normals on each molecule. A pruned tree o f possible bound configurations is built up using successive considera tion of larger and larger triplets. The best scoring configurations ar e then passed through a free-energy screen where the lowest energy mem ber is selected as the predicted native state. The free energy approxi mation is derived from observations of surface burial by atom pairs ac ross the interface of known enzyme/inhibitor complexes. The occurrence of specific atom-atom surface burial, for a set of complexes with wel l-defined secondary structure both in the bound and unbound states, is parameterized to mimic the free energy of binding. The docking proced ure guides the inhibitor into its native state using orientation and d istance-dependent functions that reproduce the ideal model of free ene rgies with an average rms deviation of 0.9 kcal/mol, For all systems s tudied, this docking procedure identifies a single, unique minimum ene rgy configuration that is highly compatible with the native state. (C) 1996 Wiley-Liss, Inc.