INFLUENCE OF AN ANTIVIRAL COMPOUND ON THE TEMPERATURE-DEPENDENCE OF VIRAL PROTEIN FLEXIBILITY AND PACKING - A MOLECULAR-DYNAMICS STUDY

The antiviral activity of compounds that bind an internal pocket of pi cornaviruses is due in part to stabilization of the protein capsid and inhibition of the uncoating process required for virus replication. I nformation on the basis for this structural stabilization of the virus capsid is important to elucidate the mechanism of antiviral action an d provide insights into the disassembly process. It has been proposed that this stabilization is entropically based, since binding the nonpo lar antiviral compound increases the compressibility, and thus the con formational flexibility, of the virus. Such a proposal predicts a diff erence in the temperature dependence of the atomic positional fluctuat ions for free virus and drug-bound virus; nonpolar interactions are we aker and less directional, and would give rise to greater conformation al disorder at low temperature. Further, the transition that has been observed in globular proteins to a state resembling a frozen liquid, i n which the protein is considered ''trapped'' in potential energy well s, is predicted to occur at lower temperature when the antiviral compo und is bound. Results described here from computer simulations of rhin ovirus over a range in temperature show these predicted changes in con formational disorder and the temperature of the transition in mobility . In addition to providing independent support for the above proposal for antiviral activity, these results indicate that the mobility trans ition of a protein can be controlled by the binding of an appropriate ligand, an effect not previously reported. (C) 1998 Academic Press Lim ited.