Occluded molecular surface analysis of ligand-macromolecule contacts: application to HIV-1 protease-inhibitor...

Herein is described a method of quantifying and visualizing ligand-macromolecule contacts with the occluded surface algorithm by utilizing Connolly's van der Waals molecular surface dots together with the associated normals, to scoop out surrounding macromolecule atoms within a distance of 6.4 A from any ligand atom. On the basis of the intersections of surface normals with the van der Waals spheres of surrounding macromolecule atoms, the van der Waals molecular surface area for each atom is divided into occluded and nonoccluded surface areas. Also, we calculate a packing parameter for each occluded surface, measuring the closeness of the occluded surface against the macromolecule atom in contact. From the partial charges of ligand and macromolecule atoms and the occluded and nonoccluded surface areas due to the contact, we were able to identify favorable and unfavorable contacts. From the value of occluded surface constant, nonoccluded surface constant, and solvent-exposed constant for ligands, we qualitatively rank order the binding of ligands to the same target. From the individual parameters, group parameters for groups of atoms in a ligand or for each residue in a ligand-binding pocket of a macromolecule could be calculated. The group and the residue-based parameters could be used in structure-based ligand design and protein engineering experiments. In this paper, we present our analysis of ligand-macromolecule contacts, using five X-ray crystal structures of HIV-1 protease-ligand complexes.