Molecular dynamics investigation of the effect of an antiviral compound onhuman rhinovirus

The factors that influence the enhanced stability observed experimentally o f human rhinovirus 14 (HRV14) upon binding a hydrophobic antiviral drug hav e been investigated by molecular dynamics. Simulations centered about the H RV14 drug-binding pocket allow the reliable assessment of differences in ca psid protein motions of HRV14 and drug-bound HRV14. We propose that the exp erimentally observed stabilization of the ligated virus arises from higher entropy, rather than enthalpy. Time-averaged interaction energies between t he viral protein and molecules occupying the pocket are less favorable in t he presence of the drug, consistent with the proposal that the observed sta bility arises from entropic effects. Interaction energies characterizing su bunit-subunit contacts within one viral protomer are found to be substantia lly stronger than those between two protomers. Such distinction in subunit interaction would have clear implications on assembly and disassembly. Drug binding is found to affect large-scale, collective properties, while leavi ng local atomic properties unperturbed. Specifically, the simulations revea l a weakening of long-range correlations in atomic motions upon drug bindin g. On the other hand, neither the fast time scale RMS fluctuations of indiv idual atomic positions nor the fluctuation build-up curves from the capsid P-sandwich forming the drug-binding pocket show a consistent distinction be tween the drug-bound and drug-free viral simulations. Collectively, the det ailed description available from the simulations provides an understanding of the experimental observations on the drug-induced changes in thermal sta bility and protease sensitivity reported for picornaviruses. The predicted significance of binding entropy can be explored experimentally and should b e considered in the design of new antiviral compounds.