Molecular dynamics studies of solvated globular proteins, human rhinovirus (HRV) and HRV-drug complexes, are proposed to elucidate certain dynamical and physical events associated with (1) protein structural stabilization, (2) the inhibition of viral uncoating by antiviral compounds, (3) binding of the compounds, and (4) molecular recognition of different viral serotypes or different antiviral compounds. Stabilization of protein tertiary and quaternary structure encompasses a number of factors, one of which is packing. Based on recently noted correlations between entropy/enthalpy of folding and compressibility, similar to correlations with heat capacity now realized for some years, Dr. Post hypothesizes that compressibility and density fluctuations allows this hypothesis to be investigated by molecular dynamics simulations. How WIN compounds, one class of antiviral agents that bind an internal pocket of the HRV protein capsid, interfere with the viral disassembly process may be related to compressibility as well. In the case of the complex HRV14-WIN52084, molecular dynamics simulations of a small spherical region centered on the drug-binding pocket revealed a novel basis for structural stabilization by the antiviral compounds: an increase in the intrinsic isothermal compressibility for the viral complex. These results suggest that there is entopic stabilization of the native capsid structure, as opposed to an increase in a kinetic barrier to uncoating. Dr. Post proposes further examination of this hypothesis by the study of other complexes. Part of this proposal focuses on the disassembly process of rhinovirus, and requires the study of the whole virus capsid in order to probe interactions between protein subunits. This work will be accomplished by exploiting the viral symmetry and with high-performance computing. How the drug molecules enter the internal pocket, and molecular recognition between different viral serotypes and drug compounds, will be examined by simulation methods, including free energy perturbation techniques. These computational studies provide a starting point to integrate the factors of energetics, compressibility, transient conformations and recognition, for the purpose of understanding antiviral activity and viral disassembly. A more complete description of these processes would increase our understanding of antiviral activity and uncoating, thereby assisting the design of improved antiviral compounds.
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