title: On the mechanism of HRV-14 antiviral compounds: "slow growth" as a conformational search procedure.
abstract: We report a novel conformational search procedure that is used to investigate the binding mechanism of a member of the WIN class of antiviral compounds. A simple hypothesis of important residues in the binding site based on differences in drug-free and drug-bound X-ray structures along with more elaborate models, ultimately including the entire virus, is considered. Our search method is a variant of slow-growth molecular dynamics used in free energy simulations and gives rise to local motion in the protein backbone of up to 3 A. This technique involves the scaling of drug-protein interaction energies over time periods of 10-100 ps and gives rise to local motion in the protein backbone. In addition, we have used high-temperature dynamics with periodic quenching to generate low-energy conformations with backbone displacements in the crystallographic binding region of up to 7 A from the native structure. Mechanism of binding, hydrogen-bond stabilization of active-site conformations, concerted drug-protein motions, and the mode of virion stabilization are addressed in relation to our ligand induced and high-temperature conformational search procedures. A loop-cap like mechanism is consistent with the results of our study. A large movement of the "active-site" residues is shown to be theoretically possible and provides a greater access for entry of the drug into its binding pocket than seen in the available crystal structures.
authors.affiliation: Department of Chemistry, University of Houston, Texas 77204-5641.
authors.forename: M
authors.initials: M
authors.lastname: Guha-Biswas
authors.forename: M
authors.initials: M
authors.lastname: Holder
authors.forename: B M
authors.initials: BM
authors.lastname: Pettitt
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018360:Crystallography, X-Ray; D004563:Electrochemistry; D006860:Hydrogen Bonding; D007555:Isoxazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D015394:Molecular Structure
chemical_list: D000998:Antiviral Agents; D007555:Isoxazoles; C045978:disoxaril