Protein Stability and Antiviral Activity in Human Rhinovirus

本申请提出了与以下相关的小核糖核酸病毒的性质的计算研究： 抗病毒活性和受体识别，以及球形颗粒的可压缩性和结构稳定性 proteins.小核糖核酸病毒科病毒家族的成员是广谱人类感染性疾病的病原体。 以及由附着于细胞表面受体引发的动物疾病。相当大的努力集中在 开发针对小核糖核酸病毒的抗病毒化合物。抗病毒活性的机制， 受体识别的物理/化学基础将通过分子动力学模拟研究来检验。 需要解决的具体问题包括抗病毒化合物结合在一个细胞中的长期动态效应。 人鼻病毒（HRV）内部疏水口袋对病毒构象特性的影响。基于 根据以前的结果，提出抗病毒化合物的长期作用改变了 在5重对称轴上的残基，并且这种反应有助于WIN的抗病毒活性 化合物.我们将使用大规模模拟来探索这个问题。此外，自由能方法 将用于探索HRV的细胞间粘附分子1（ICAM-1）特异性的基础， 柯萨奇病毒（CV）。小核糖核酸病毒受体结构测定的新进展 复合物从冷冻电子显微镜重建提供了一个新的机会， 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， 这不能从结构中解释，将使用自由能模拟来检查。最后， 抗病毒活性和受体识别的机制与基本物理性质有关 蛋白质，和计算研究的基础上的问题有关的稳定性，可压缩性和溶剂化 也提出了。MD模拟的详细信息将被用来阐明一个新的 通过定义蛋白质可压缩性和能量学之间的对应关系， 蛋白质中埋藏电荷的稳定性。水合沃茨的压缩性与蛋白质的分析 还将探测溶液压缩率。

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.