PROTEIN STABILITY IN HUMAN RHINOVIRUS

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Computational studies on protein stability and conformational dynamics of capsid proteins from human rhinovirus (HRV) and small globular patterns are proposed. As well as the mean thermodynamic properties enthalpy and entropy, fluctuation properties such as heat capacity and compressibility are useful for understanding contributions to stability. Compressibility of globular proteins will be studied using molecular dynamics simulations to elucidate the basis for the variation in measured compressibility values among proteins. Regarding HRV, the capsid proteins present an interesting case study in stability in that the capsid must be conformationally variable to meet the demands of the viral life cycle. The virus is stable outside the host cell, yet also capable of releasing RNA, or uncoating, once the virus has entered the cell. This switch in conformation is thought to be triggered by contact with the cell receptor, and to be effected by some antiviral compounds. HRV is a member of the picornavirus family and the leading causative agent for the common cold. Other important human pathogens among the members of the picornaviruses are poliovirus, coxsackie virus and hepatitis A virus. Several features associated with the uncoating process will be investigated by the proposed studies. A hydrophobic pocket in VP1 binds long alkylchain molecules, or pocket-factors. This hydrophobic pocket in VP1 also is the site for binding antiviral compounds. Ligand effects on compressibility, energetics and protein-protein interactions will be characterized for a variety of HRV14 complexes. Different models have been generated to explain the receptor-induced conformational changes of picornaviruses and the mechanism of uncoating. Molecular dynamics simulations provide a means to examine in atomic detail certain features of these models. We seek a description that provides insight into physical behavior of the viral capsid proteins and their complexes with antiviral compounds or host cell receptor.