Protein Stability and Antiviral Activity in Human Rhinovirus

人鼻病毒的蛋白质稳定性和抗病毒活性

• 批准号: 7346924
• 负责人: CAROL B. POST
• 金额: $ 22.44万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7346924
• 关键词: Abbreviations; Accounting; Address; Adhesives; Amino Acid Receptors; Animal Diseases; Antiviral Agents; Binding; Capsid; Cell Surface Receptors; Charge; Chemicals; Common Cold; Complex; Computer Analysis; Coxsackie Viruses; Cryoelectron Microscopy; Dependence; Development; Entropy; Family Picornaviridae; Free Energy; Grant; Heating; Human; Human poliovirus; Hydration status; Intercellular adhesion molecule 1; Investigation; Knowledge; Link; Methods; Modeling; Molecular; Mutagenesis; Mutation; Paper; Pharmacologic Substance; Physical activity; Polioviruses; Process; Property; Protein Analysis; Proteins; Range; Research; Research Personnel; Research Project Grants; Rhinovirus; Roentgen Rays; Serotyping; Solutions; Specificity; Structural Protein; Structure; Testing; Thermodynamics; Time; Variant; Viral Proteins; Virus; Water; base; computer studies; enthalpy; globular protein; insight; large scale simulation; member; molecular dynamics; physical property; programs; receptor; reconstruction; response; rhinovirus viral protein 1; simulation; small molecule

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.

该应用程序提出了有关与picornaviruses属性的计算调查 抗病毒活性和受体识别，以及可压缩性和结构：球状的稳定性 蛋白质。 Picornaviridae病毒家族的成员是一系列人类的致病药物 和通过附着在细胞表面受体上引发的动物疾病。巨大的努力集中在 开发针对picornaviruses的抗病毒化合物。抗病毒活性的机制， 分子动力学仿真研究将检查受体识别的物理/化学基础。 要解决的具体问题包括抗病毒化合物结合的远程动态作用 人类鼻病毒（HRV）对病毒构象性质的内部疏水袋。基于 在先前的结果上，有人提出抗病毒化合物的长距离作用改变了动力学 5倍对称轴的残留物，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探讨这个问题。此外，自由能的方法 将用于探测HRV的细胞间粘附分子1（ICAM-1）特异性的基础 Coxsackievivirus（CV）。确定Picornavirus受体的结构的最新进展 冷冻电子显微镜重建的复合物为计算提供了新的机会 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， 无法从结构中解释，将使用自由能模拟检查。最后， 抗病毒活性和受体识别的机制与基本物理特性有关 蛋白质和基于与稳定性，可压缩性和溶剂化有关的问题的计算研究 也提出了。 MD模拟的详细信息将被利用以阐明新的 通过定义的基础，可以在 在蛋白质中埋葬电荷的稳定。水合水的可压缩性和蛋白质的分析 也将探测解决方案的压缩性。