A NOVEL BASIS FOR CAPSID STABILIZATION BY ANTIVIRAL COMPOUNDS

Picornaviruses are inactivated by a family of hydrophobic drugs that b ind at an internal site in the viral capsid and inhibit viral uncoatin g. A basis for the capsid stabilization previously unrecognized is rev ealed by molecular dynamics simulations of the antiviral drug WIN52084 s bound to a hydrophobic. pocket of solvated human rhinovirus 14. Isot hermal compressibilities of the complex and human rhinovirus 14 withou t the antiviral drug calculated from density fluctuations show that th e presence of WIN52084s increases the compressibility of the viral cap sid near the antiviral drug. This counterintuitive result is understan dable on the basis of the empirical evidence of thermal melting temper atures and protein-folding entropies of globular proteins. Based on th is evidence, we propose that a larger compressibility from drug bindin g confers greater thermal stability to capsid proteins by increasing t he conformational entropy of capsids, thereby diminishing the entropy gain with uncoating. We suggest that compressibility is fundamental to the structural integrity of viral capsids and that examination of com pressibility and antiviral activity will provide insights into the dis assembly process. (C) 1995 Academic Press Limited