Army High-Performance Computing Research Center for the U.S. Army Medical Research Institute of Infectious Diseases   [open pdf - 1MB]

Computer simulation methods have been used to analyze the structural interactions and energetics governing the binding of substrates formycin 5'- monophosphate (FMP) and adenyl(3' to 5')guanosine (ApG) in the ricin A-chain active site. The studies undertaken showed the average simulation structures of the substrate-bound enzyme to be in good accord with the observed X-ray crystal structures in reproducing an overall binding mode. However, for FMP there are significant differences in the location and binding of the phosphate group. Free-energy simulation methods have been employed to explore several structural motifs of FMP which would have a greater binding affinity for the active site. It is shown that ricin A-chain has a preference for FMP over analogs 2-amino formycin 5'-phosphate and 2-hydroxyl formycin 5'-phosphate. Using 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 design of new ligands for ricin. These potential antidotes are being further evaluated by molecular-dynamics simulations to determine the relative binding affinities

Public Domain
Media Type:
Help with citations