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先前在DNA复制和相关生化过程的研究中开发和测试的计算技术。这些计算机模拟将由于不同的因素而系统地检查化学步骤的激活屏障的变化，包括远处pol B残基的点突变，并由-c x y-组取代p -y桥接氧的氧气，其中X. y = H，CH3，CH3，CI，CI，CI，CI，BR或N3，以及Deoxyribose Rescore of Primer of Primer或dnt的脱氧二氧化氢蛋白酶的替代。另外，将通过具有扩展的模拟时间的经过验证的计算策略来研究基材在其地面和过渡状态配置中的底物结合的计算。模拟的结果（包括TS结构和电荷分布以及仿真协议）将形成一个数据库，该数据库将包括许多实验检验的预测以及用于生成这些预测的假设和理论模型的列表。该数据库将在线访问，将不断通过新的实验和计算结果进行更新，帮助选择最佳模型和仿真策略，并最终了解原子级别DNA聚合酶在功能上重要的属性。此外，比较研究将有助于选择用于计算抑制剂和突变筛选的最有效方法。