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

确定 He 的 RNA 聚合酶变构的分子起源

• 批准号: 8528296
• 负责人: Brittny Davis
• 金额: $ 3.58万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE COUNTY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-07 至 2016-09-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8528296
• 关键词: Active Sites; Adverse effects; Affect; Amino Acids; Binding; Binding Sites; Biochemical; Chronic; Cirrhosis; Contracts; DNA-Directed RNA Polymerase; Data; Development; Disease; Drug Targeting; Effectiveness; Enzymes; Exhibits; Frequencies; Goals; Hepatitis C; Hepatitis C virus; Individual; Knowledge; Life; Ligand Binding; Ligands; Link; Liver; Malignant neoplasm of liver; Mediating; Molecular; Molecular Biology; Molecular Conformation; Molecular Models; Motion; Mutation; Outcome; Patients; Play; Point Mutation; Polymerase; Polymerase Gene; Process; Property; Proteins; RNA; Research; Roentgen Rays; Role; Sampling; Structure; Testing; Thermodynamics; United States; Viral; Work; abstracting; base; enzyme activity; improved; inhibitor/antagonist; molecular dynamics; molecular modeling; novel; prevent; public health relevance; small molecule; tool; viral RNA

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.

描述（由申请人提供）：确定丙型肝炎病毒 RNA 聚合酶变构的分子起源 摘要丙型肝炎病毒（HCV）感染全世界 1.7 亿人，在美国感染约 3-400 万人。迄今为止，这种疾病无法治愈，25% 的 HCV 感染者患有慢性肝病 例如肝硬化或肝癌。 HCV 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点。已鉴定出几种抑制 NS5B 并在活性位点外部结合的小分子；这些被称为变构抑制剂。已鉴定出五个不同的变构结合位点，并且存在与各种抑制剂结合的 NS5B 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，通过使用分子动力学模拟研究游离状态和与各种抑制剂结合的酶，可以了解变构抑制剂对 NS5B 功能特性的影响。分子动力学是研究这个问题的最佳工具，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。在此过程中，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且更有效的 NS5B 抑制剂，并最终更好地治疗 HCV。