The factors that influence the enhanced stability
observed experimentally of human rhinovirus 14 (HRV14)
upon binding a hydrophobic antiviral drug have been investigated
by molecular dynamics. Simulations centered about the HRV14
drug-binding pocket allow the reliable assessment of differences
in capsid protein motions of HRV14 and drug-bound HRV14.
We propose that the experimentally observed stabilization
of the ligated virus arises from higher entropy, rather
than enthalpy. Time-averaged interaction energies between
the viral protein and molecules occupying the pocket are
less favorable in the presence of the drug, consistent
with the proposal that the observed stability arises from
entropic effects. Interaction energies characterizing subunit–subunit
contacts within one viral protomer are found to be substantially
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 leaving local
atomic properties unperturbed. Specifically, the simulations
reveal a weakening of long-range correlations in atomic
motions upon drug binding. On the other hand, neither the
fast time scale RMS fluctuations of individual atomic positions
nor the fluctuation build-up curves from the capsid β-sandwich
forming the drug-binding pocket show a consistent distinction
between the drug-bound and drug-free viral simulations.
Collectively, the detailed description available from the
simulations provides an understanding of the experimental
observations on the drug-induced changes in thermal stability
and protease sensitivity reported for picornaviruses. The
predicted significance of binding entropy can be explored
experimentally and should be considered in the design of
new antiviral compounds.