Binding of an antiviral agent to a sensitive and a resistant human rhinovirus. Computer simulation studies with sampling of amino acid side-chain conformations: I. Mapping the rotamers of residue 188 of viral protein 1

Abstract

The mutation of valine 188 to leucine in the viral protein 1 of human rhinovirus 14 renders the virus resistant to certain antiviral compounds. Thermodynamic-cycle perturbation theory provides a means of calculating the difference in the binding free energies of an antiviral compound to the wild-type virus and to the mutant virus. In calculating the relevant free-energy differences in molecular dynamics simulations, it is important to sample the multiple rotational isomers of residue 188 correctly. In general, these rotamers will not be fully sampled during a single molecular dynamics simulation. However, the contributions of all the rotamers to the free-energy differences associated with mutation of residue 188 may be considered explicitly once they have been identified and their relative free energies determined. Therefore, we describe here the mapping of the rotamers of residue 188 by steric-bump search and energy minimization techniques, and by the computation of potentials of mean force (p.m.f.s.) using umbrella sampling. The usefulness, validity and efficiency of these methods of examining rotameric states is discussed. Adiabatic mapping by energy minimization was found to be unreliable for this residue due to the small magnitude of its interactions with the surrounding protein atoms. Ambiguities in the adiabatic maps were resolved by computing p.m.f.s. The p.m.f. for valine 188 in the unliganded wild-type virus shows a minimum corresponding to the crystallographically observed conformation of valine 188. The p.m.f.s. for valine 188 in the liganded virus and for leucine 188 in the unliganded mutant virus suggest that the experimentally observed conformations may be interpreted as averages of a number of conformations corresponding to those at the minima in the p.m.f.s. The calculations suggest also that the conformation of leucine 188 may change when the ligand binds. The use of the calculated p.m.f.s. to compute the difference in the free energy of binding of an antiviral compound to the wild-type and mutant rhinoviruses is described in the accompanying article.