PROTEIN STABILITY IN HUMAN RHINOVIRUS

提出了人鼻病毒（HRV）衣壳蛋白的蛋白质稳定性和构象动力学的计算研究。除了平均热力学性质（焓和熵）之外，波动性质（如热容和可压缩性）也有助于理解对稳定性的贡献。球状蛋白的可压缩性将用分子动力学模拟来研究，以阐明蛋白质之间可压缩性测量值变化的基础。关于HRV，衣壳蛋白在稳定性方面提供了一个有趣的研究案例，因为衣壳必须是构象可变的才能满足病毒生命周期的需求。病毒在宿主细胞外是稳定的，但一旦病毒进入细胞，也能够释放RNA或脱壳。这种构象的转换被认为是通过与细胞受体接触而触发的，并受到一些抗病毒化合物的影响。HRV是小核糖核酸病毒家族的一员，也是普通感冒的主要病原体。小核糖核酸病毒成员中其他重要的人类病原体是脊髓灰质炎病毒、柯萨奇病毒和甲型肝炎病毒。提出的研究将调查与脱涂层过程相关的几个特征。VP1中的疏水性口袋结合长烷基链分子或口袋因子。VP1中的这个疏水袋也是结合抗病毒化合物的位点。配体对各种HRV14复合物的可压缩性、能量学和蛋白质-蛋白质相互作用的影响将被表征。不同的模型已经产生来解释受体诱导的小核糖核酸病毒的构象变化和脱壳机制。分子动力学模拟提供了一种在原子细节上检查这些模型的某些特征的方法。我们寻求一种描述，以提供对病毒衣壳蛋白及其与抗病毒化合物或宿主细胞受体的复合物的物理行为的见解。

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.