The particle concept: Placing discrete water molecules during protein-ligand docking predictions

Water is known to play a significant role in the formation of protein-ligan d complexes. In this paper, we focus on the influence of water molecules on the structure of protein-ligand complexes, We present an algorithmic appro ach, called the particle concept, for integrating the placement of single w ater molecules in the docking algorithm of FLEXX, FLEXX is an incremental c onstruction approach to ligand docking consisting of three phases: the sele ction of base fragments, the placement of the base fragments, and the incre mental reconstruction of the ligand inside the active site of a protein, Th e goal of the extension is to find water molecules at favorable places in t he protein-ligand interface which may guide the placement of the ligand. In a preprocessing phase, favorable positions of water molecules inside the a ctive site are calculated and stored in a list of possible water positions. During the incremental construction phase, water molecules are placed at t he precomputed positions if they can form additional hydrogen bonds to the ligand. Steric constraints resulting from the water molecules as well as th e geometry of the hydrogen bonds are used to optimize the ligand orientatio n in the active site during the reconstruction process. We have tested the particle concept on a series of 200 protein-ligand complexes. Although the average improvement of the prediction results is minor, we were able to pre dict water molecules between the protein and the ligand correctly in severa l cases. For instance in the case of HIV-1 protease, where a single water m olecule between the protein and the ligand is known to be of importance in complex formation, significant improvements can be achieved. (C) 1999 Wiley -Liss, Inc.