Department of Plant Genetics, Weizmann Institute of Science, Rehovot, ISRAEL
lpsobol@wiccmail.weizmann.ac.il
Surface complementarity between ligand and receptor is the guiding principle for ligand docking in our approach. Surface complementarity incorporates information about the shape and chemical nature of the atoms of the interacting molecules. We have optimized the definition of surface complementarity and show how it can be used to dock ligands (taking some account of receptor flexibility), analyze binding modes, and suggest new ligands. We have tested the program with a wide range of ligands and ligand - protein complexes for which the coordinates of the holo- and, in some cases, aporeceptor, are available. The advantages of using surface complementarity are particularly apparent when ligands are docked into spacious receptor pockets. In such cases, our method performs well because the definition of contact surface allows loose contacts (up to a solvent-separated distance apart) to be considered and it optimizes favourable polar contacts, both loose and tight.
In cases where local side chain flexibility is required for ligand docking, the program is helpful in determining a ligand position close to that experimentally observed and identifies which residues reorient on ligand binding. In addition, surface complementarity, with a different atom-type substituted at each atom position in the docked ligand, can be calculated. The program provides lists of residues in contact with the ligand and putative hydrogen bonds between receptor and ligand. These lists permit an analysis of all contributions to the complementarity function, clarify factors governing complex formation and assist in the design of improved ligands.