Determining the Molecular Origins of Allostery for the RNA Polymerase from the He

描述(申请人提供)：确定丙型肝炎病毒RNA聚合酶变构的分子来源丙型肝炎病毒(丙型肝炎病毒)感染全球1.7亿人，美国境内约300-400万人。到目前为止，这种疾病还没有治愈的方法，25%的丙型肝炎病毒携带者患有慢性肝病 比如肝硬变或肝癌。丙型肝炎病毒RNA聚合酶(基因产物NS5B)因其在病毒复制中的重要性而成为药物靶标。已经确定了几个小分子，它们抑制NS5B并结合到活性部位之外；这些被称为别固醇抑制剂。目前已鉴定出五种不同的变构结合部位，NS5B酶与不同的抑制剂结合存在多种晶体结构。然而，仅从结构数据来看，抑制机制尚不清楚，尚未确定。我们假设，人们可以通过分子动力学模拟来研究变构抑制剂对NS5B功能性质的影响，以研究处于自由状态并与各种抑制剂结合的酶。分子动力学是研究这一问题的最佳工具，因为它可以在精细的细节水平上提供关于结构和动力学的信息。通过了解伴随配体结合的结构、动力学和热力学变化，我们希望确定NS5B变构抑制的分子起源。在这个过程中，我们将获得有关NS5B和其他病毒聚合酶如何复制RNA的重要信息。除了阐明有关酶功能和动力学之间联系的基本问题外，这些信息可能有助于开发新型和更有效的NS5B抑制剂，并最终更好地治疗丙型肝炎。

DESCRIPTION (provided by applicant): Determining the Molecular Origins of Allostery for the RNA polymerase from the Hepatitis C Virus Abstract Hepatitis C virus (HCV) infects 170 million people worldwide, and approximately 3-4 million people within the United States. To date, there is no cure for this disease, and 25% of individuals living with HCV contract chronic liver ailments such as cirrhosis or liver cancer. The HCV RNA polymerase (gene product NS5B) has become a drug target because of its importance in viral replication. Several small molecules have been identified that inhibit NS5B and bind outside of the active site; these are referred to as allosterc inhibitors. There are five different allosteric binding sites that have been identified, and severa crystal structures of NS5B enzyme bound to various inhibitors exist. However, a mechanism of inhibition is unclear from the structural data alone and has yet to be conclusively determined. We hypothesize that one can understand the effect of allosteric inhibitors on the functional properties of NS5B by using molecular dynamics simulations to study the enzyme in a free state and bound to various inhibitors. Molecular dynamics is an optimal tool to study this problem because it can provide information about both structure and dynamics at a level of fine detail. By understanding the structural, dynamic, and thermodynamic changes that accompany ligand binding, we hope to determine the molecular origins of allosteric inhibition in NS5B. In the process we will gain essential information on how NS5B and other viral polymerases replicate RNA. Besides illuminating fundamental questions regarding the link between enzyme function and dynamics, this information may aid in the development of novel and more effective inhibitors for NS5B, and ultimately better treatments for HCV.