Protein Stability and Antiviral Activity in Human Rhinovirus

描述（由申请人提供）：本申请提出了与抗病毒活性和受体识别相关的小核糖核酸病毒性质的计算研究，以及球状蛋白质的可压缩性和结构稳定性的计算研究。小核糖核酸病毒科病毒家族的成员是通过附着于细胞表面受体而引发的广谱人类和动物疾病的病原体。相当大的努力集中在针对小核糖核酸病毒的抗病毒化合物的开发上。抗病毒活性的机制，和受体识别的物理/化学基础将通过分子动力学模拟研究进行检查。要解决的具体问题包括在人鼻病毒（HRV）的内部疏水口袋中结合的抗病毒化合物对病毒构象特性的长期动态影响。基于以前的结果，有人提出，抗病毒化合物的长程效应改变在5倍对称轴的残基的动力学，这种响应有助于WIN化合物的抗病毒活性。我们将使用大规模模拟来探索这个问题。此外，自由能方法将用于探测细胞间粘附分子1（ICAM-1）对HRV和柯萨奇病毒（CV）特异性的基础。最近的进展，在确定的小核糖核酸病毒受体复合物的结构，从冷冻电子显微镜重建提供了一个新的机会，计算分析，以阐明受体识别。受体氨基酸突变对病毒衣壳结合的影响，不能从结构上解释，将使用自由能模拟进行检查。最后，抗病毒活性和受体识别的机制与蛋白质的基本物理性质，和计算研究的基础上有关的稳定性，可压缩性和溶剂化的问题也提出了建议。MD模拟的详细信息将被利用来阐明一个新认识的蛋白质压缩性和能量之间的对应关系，通过定义的基础上稳定的蛋白质中的掩埋电荷。并探讨水合沃茨的压缩性及蛋白质溶液压缩性的分析。

DESCRIPTION (provided by applicant): This application proposes computational investigations of the properties of picornaviruses associated with antiviral activity and receptor recognition, and of the compressibility and structural: stability of globular proteins. Members of the virus family of Picornaviridae are causative agents of a broad spectrum of human and animal diseases initiated by attachment to cell surface receptors. Considerable effort has focused on the development of antiviral compounds against picornaviruses. The mechanism of antiviral activity, and the physical/chemical basis of receptor recognition will be examined by molecular dynamics simulation studies. Specific issues to be addressed include the long-range dynamic effects of antiviral compounds binding in an internal hydrophobic pocket of human rhinovirus (HRV) on the conformational properties of the virus. Based on previous results, it is proposed that long-range effects of antiviral compounds alter the dynamics of residues at the 5-fold symmetry axis, and that this response contributes to the antiviral activity of WIN compounds. We will explore this question using large-scale simulations. In addition, free-energy methods will be used to probe the basis of intercellular adhesion molecule 1 (ICAM-1) specificity for HRV and coxsackievirus (CV). Recent progress in the determination of structures of the picornavirus-receptor complexes from cryo-electron microscopy reconstruction provide a new opportunity for computational analysis to elucidate receptor recognition. Effects of receptor amino acid mutations on virus capsid binding, which cannot be explained from the structures, will be examined using free energy simulations. Finally, mechanisms of antiviral activity and receptor recognition are associated with fundamental physical properties of proteins, and computational studies based on questions related to stability, compressibility and solvation are also proposed. The detailed information of MD simulations will be exploited to elucidate a newly recognized correspondence between protein compressibility and energetics by defining the basis for stabilization of buried charge in proteins. The compressibility of hydration waters and analysis of protein solution compressibilities will also be probed.