J. MoL BioL (1995) 248,.459-477 JMB A Geometry-based Suite of Molecular Docking Processes Daniel Fischer 1,2, Shuo Liang Lin 3, Haim L. Wolfson 1 and Ruth Nussinov 2,3. JComputer Science Department, School of Mathematical Sciences, Tel Aviv University, Tel Aviv 69978, Israel 2Sackler Institute of Molecular Medicine, Tel Aviv University Tel Aviv 69978, Israel 3Laboratory of Mathematical Biology, NCI-FCRF, Bldg 469, Rm 151, Frederick, MD 21702, U.S.A. *Corresponding author We have developed a geometry-based suite of processes for molecular docking. The suite consists of a molecular surface representation, a docking algorithm, and a surface inter-penetration and contact filter. The surface representation is composed of a sparse set of critical points (with their associated normals) positioned at the face centers of the molecular surface, providing a concise yet representative set. The docking algorithm is based on the Geometric Hashing technique, which indexes the critical points with their normals in a transformation invariant fashion preserving the multi-element geometric constraints. The inter-penetration and surface contact filter features a three-layer scoring system, through which docked models with high contact area and low clashes are funneled. This suite of processes enables a pipelined operation of molecular docking with high efficacy Accurate and fast docking has been achieved with a rich collection of complexes and unbound molecules, including protein-protein and protein-small molecule associations. An energy evaluation routine assesses the intermolecular interactions of the funneled models obtained from the docking of the bound molecules by pairwise van der Waals and Coulombic potentials. Applications of this routine demonstrate the goodness of the high scoring, geometrically docked conformations of the bound crystal complexes. Keywords: molecular docking; docking of bound and unbound complexes; protein-protein docking; protein-drug docking; molecular surface matching Introduction Geometric complementarity is a central issue in biomolecular recognition. Tightly matched surfaces between bound molecules close an appreciable area of interface to the medium, gaining stability for the complex from hydrophobic effects. The complemen- tary geometry reflects the effect of van der Waals interactions, which are very sharp at short distances. A tight, fairly large interface constitutes a necessary condition of a stable complex, upon which a screening of possible conformations would rapidly converge to those feasible for further physical, chemical and biological examinations. Investigating molecular recognition in such a relayed mode can be far more efficient than ab initio methods for larger molecular systems. Docking methods have emerged during the last few years that are able to reproduce near-native conformations on the basis of geometri- Present address: D. Fischer, Laboratory of Mathematical Biology, NCI-FCRF, Bldg 469, Rm 151, Frederick, MD 21702, U.S.A. cal complementarity (Fischer et al., 1993; Lin et al., 1994; Norel et al., 1994a,b; Connoll}¢ 1986; Cherfils et al., 1991; Jiang & Kim, 1991; Shoichet & Kuntz, 1991; Wang, 1991; Bacon & Moult, 1992; Katchalski- Katzir et al., 1992; Walls & Sternberg, 1992). Geometric docking is exceedingly complex, due to the fact that computational costs increase exponen- tially with the degrees of freedom of the molecular system. With hundreds to thousands of atoms to move, the number of possible conformations is astronomical. Any practical docking method has to apply serious constraints to the system. Rigid body approximation that freezes all the" degrees of freedom but three translations and three rotations is currently the choice of most of the general docking methods. For proteins, it has been argued that the approximation is justified by the similarity of the crystallographic structures between the bound and the unbound proteins (Janin & Chothia, 1990; Cherfils & Janin, 1993), while cases exist where more substantial conformational changes have been observed that may need a different methodology Even when molecules are treated as rigid bodies, a 0022-2836/95/170459-19 $08.00/0 r~ 1995 Academic Press Limited