Army High-Performance Computing Research Center for the U.S. Army Medical Research Institute of Infectious Diseases

Abstract : Molecular-simulation methods in conjunction with X-ray crystallography and interactive computer graphics have been employed for determining key structural and functional features of ligand-bound ricin A- chain. Particular detail has been given to analyzing the structural interactions and energetics governing the binding of two nucleotide ligands, formycin 5'- monophosphate (FMP) and adenyl-3',5'-guanosine (ApG), thought to mimic certain elements of the rRNA substrate. The studies undertaken showed the average simulation structures of the ligand-bound enzyme to be in good accord with the observed X-ray crystal structures in reproducing an overall binding mode. Complementary studies have been carried out aimed at exploring several structural motifs of FMP which would have a greater binding affinity for the active site and perhaps function as template for the development of transition- state analogs for ricin. Building on the binding motif of the adenine ring from the average simulation structures, several substituents have been appended to the base with removal of the ribose and phosphate group leading to the de novo design of ligands for ricin. Ricin, Molecular modeling, Protein structure-based design of enzyme inhibitors, BD, RAD IV.