A geometric approach to macromolecule-ligand interactions

Abstract We describe a method to explore geometrically feasible alignments of ligands and receptors of known structure. Algorithms are presented that examine many binding geometries and evaluate them in terms of steric overlap. The procedure uses specific molecular conformations. A method is included for finding putative binding sites on a macromolecular surface. Results are reported for two systems: the heme-myoglobin interaction and the binding of thyroid hormone analogs to prealbumin. In each case the program finds structures within 1 A of the X-ray results and also finds distinctly different geometries that provide good steric fits. The approach seems well-suited for generating starting conformations for energy refinement programs and interactive computer graphics routines.