Computational Core

计算核心

基本信息

批准号：
8591739
负责人：
ARIEH WARSHEL
金额：
$ 4.97万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-03 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8591739
关键词：
Active Sites Base Excision Repairs Binding Biochemical Biochemical Process Charge Chemical Structure Chemicals Communities Comparative Study Computational Technique Computer Analysis Computer Simulation DNA biosynthesis DNA-Directed DNA Polymerase Data Data Set Databases Deoxyribose Development Distant Docking Drug Design Electrostatics Environment Enzymes Esters Family Free Energy Generations Human Hydrogen Bonding Instruction Kinetics Methods Modeling Molecular Nucleotides Oxygen Pathway interactions Play Point Mutation Polymerase Property Protocols documentation Reaction Replication Origin Research Role Series Services Solutions Structure Testing Theoretical model Time Update analog animation aqueous base computer studies inhibitor/antagonist inorganic phosphate models and simulation mutant operation programs quantum research study response screening simulation theories

项目摘要

We will use computational techniques that were previously developed and tested by our research group in studies of DNA replication and related biochemical processes. These computer simulations will systematically examine changes in the activation barrier of the chemical step due to different factors including the effects of point mutations of distant pol B residues, to substitutions of the p-y bridging oxygen by the - C X Y - groups where X. Y = H, CH3, F, CI, Br or N3, and substitutions in the deoxyribose residues of the primer or dNTP nucleotides. Additionally, calculations of the substrate binding in its ground- and transition-state configurations will be investigated by proven computational strategies with extended simulation times. The results of the simulations (including TS structures and charge distributions as well as simulation protocols) will form a database that will include numerous experimentally-testable predictions along with the list of the assumptions and theoretical models that were used to generate these predictions. This database, which will be made accessible online, will be continually updated with new experimental and computational results, helping in selecting the best models and simulation strategies, and eventually to understanding of the functionally important properties of DNA polymerases at the atomic level. Additionally, the comparative studies will help in selecting the most effective approach for computational inhibitor and mutational screening.

我们将使用我们的研究小组之前开发和测试的计算技术来研究 DNA 复制和相关的生化过程。这些计算机模拟将系统地检查化学步骤的活化势垒由于不同因素而发生的变化，包括远处 pol B 残基的点突变的影响，以及 p-y 桥接氧被 -C X Y - 基团取代（其中 X. Y = H）的影响、CH3、F、Cl、Br 或 N3，以及引物或 dNTP 核苷酸的脱氧核糖残基中的取代。此外，将通过经过验证的计算策略和延长的模拟时间来研究基态和过渡态构型中底物结合的计算。模拟结果（包括 TS 结构和电荷分布以及模拟协议）将形成一个数据库，其中包括大量可通过实验测试的预测以及用于生成这些预测的假设和理论模型列表。该数据库将可在线访问，并将不断更新新的实验和计算结果，帮助选择最佳模型和模拟策略，并最终在原子水平上了解 DNA 聚合酶的重要功能特性。此外，比较研究将有助于选择最有效的计算抑制剂和突变筛选方法。