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

描述（由申请人提供）：确定来自丙型肝炎病毒的RNA聚合酶的Allostery的分子起源摘要丙型肝炎病毒（HCV）感染全世界1.7亿人，在美国约有3-4百万人。迄今为止，这种疾病还没有治愈方法，25%的HCV感染者患有慢性肝病 如肝硬化或肝癌。HCV RNA聚合酶（基因产物NS 5 B）由于其在病毒复制中的重要性而成为药物靶点。已经鉴定了几种抑制NS 5 B并结合在活性位点之外的小分子;这些被称为变构抑制剂。已经鉴定了五种不同的变构结合位点，并且存在与各种抑制剂结合的NS 5 B酶的几种晶体结构。然而，仅从结构数据来看，抑制机制尚不清楚，尚未最终确定。我们假设，可以理解的变构抑制剂的功能特性的NS 5 B的影响，通过使用分子动力学模拟研究酶在自由状态下，并绑定到各种抑制剂。分子动力学是研究这一问题的最佳工具，因为它可以提供有关结构和动力学的详细信息。通过了解结构，动力学和热力学的变化，配体结合，我们希望能确定在NS 5 B变构抑制的分子起源。在这个过程中，我们将获得关于NS 5 B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NS 5 B抑制剂，并最终更好地治疗HCV。

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.