PROTEIN STRUCTURE STABILIZATION AND ACTIVITY IN HUMAN RH

描述：溶剂化球状蛋白的分子动力学研究， 人鼻病毒(HRV)和HRV-药物复合体被提议阐明 与(1)蛋白质结构有关的某些动力学和物理事件 稳定化，(2)抗病毒化合物抑制病毒脱壳， (3)化合物的结合；(4)不同化合物的分子识别 病毒血清型或不同的抗病毒化合物。蛋白质的稳定化 三级和四级结构包括若干因素，其中之一 那就是打包。基于最近注意到的 折叠性和可压缩性的熵/焓，类似于关联式 由于热容量现在已经实现了几年，波斯特博士假设 可压缩性和密度波动允许这一假设 通过分子动力学模拟进行了研究。如何赢得化合物，一 一类结合HRV蛋白内部口袋的抗病毒药物 衣壳蛋白，干扰病毒的拆解过程可能与 可压缩性也是如此。在复合体HRV14-WIN52084的情况下， 以分子为中心的小球状区域的分子动力学模拟 药物结合口袋揭示了结构稳定的新基础 抗病毒化合物：增加固有等温线 病毒复合体的可压缩性。这些结果表明， 天然衣壳结构的对位稳定化，而不是 增加脱膜的动能阻挡。波斯特博士建议进一步 通过对其他络合物的研究来检验这一假设。部分 这项提案侧重于鼻病毒的拆解过程，并要求 通过对病毒全衣壳的研究，探讨病毒与病毒的相互作用 蛋白质亚基。这项工作将通过利用病毒来完成 对称性和高性能计算。药物分子是如何进入的 内部口袋，以及不同病毒之间的分子识别 血清型和药物化合物，将通过模拟方法进行检查， 包括自由能微扰技术。这些计算研究 提供了一个整合能量学因素的起点， 可压缩性、瞬变构象和识别 了解抗病毒活性和病毒分解。一个更完整的 对这些过程的描述将增加我们对抗病毒药物的理解 活性和脱膜，从而辅助设计改进的抗病毒药物 化合物。

DESCRIPTION: Molecular dynamics studies of solvated globular proteins, human rhinovirus (HRV) and HRV-drug complexes, are proposed to elucidate certain dynamical and physical events associated with (1) protein structural stabilization, (2) the inhibition of viral uncoating by antiviral compounds, (3) binding of the compounds, and (4) molecular recognition of different viral serotypes or different antiviral compounds. Stabilization of protein tertiary and quaternary structure encompasses a number of factors, one of which is packing. Based on recently noted correlations between entropy/enthalpy of folding and compressibility, similar to correlations with heat capacity now realized for some years, Dr. Post hypothesizes that compressibility and density fluctuations allows this hypothesis to be investigated by molecular dynamics simulations. How WIN compounds, one class of antiviral agents that bind an internal pocket of the HRV protein capsid, interfere with the viral disassembly process may be related to compressibility as well. In the case of the complex HRV14-WIN52084, molecular dynamics simulations of a small spherical region centered on the drug-binding pocket revealed a novel basis for structural stabilization by the antiviral compounds: an increase in the intrinsic isothermal compressibility for the viral complex. These results suggest that there is entopic stabilization of the native capsid structure, as opposed to an increase in a kinetic barrier to uncoating. Dr. Post proposes further examination of this hypothesis by the study of other complexes. Part of this proposal focuses on the disassembly process of rhinovirus, and requires the study of the whole virus capsid in order to probe interactions between protein subunits. This work will be accomplished by exploiting the viral symmetry and with high-performance computing. How the drug molecules enter the internal pocket, and molecular recognition between different viral serotypes and drug compounds, will be examined by simulation methods, including free energy perturbation techniques. These computational studies provide a starting point to integrate the factors of energetics, compressibility, transient conformations and recognition, for the purpose of understanding antiviral activity and viral disassembly. A more complete description of these processes would increase our understanding of antiviral activity and uncoating, thereby assisting the design of improved antiviral compounds.