MISMATCH RECOGNITION BY MSH2-MSH6

MSH2-MSH6 的不匹配识别

• 批准号: 7956342
• 负责人: Michael Feig
• 金额: $ 0.08万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7956342
• 关键词: ATP phosphohydrolase; Accounting; Bacteria; Biomedical Research; Complex; Computer Retrieval of Information on Scientific Projects Database; Computer software; Coupling; Crystallography; DNA; DNA biosynthesis; Development; Ensure; Funding; Genetic; Goals; Grant; High Performance Computing; Institution; Lead; Mismatch Repair; Preparation; Research; Research Personnel; Resources; Signal Transduction; Source; Structure; Time; United States National Institutes of Health; base; computer studies; molecular dynamics; repaired; simulation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Post-replication DNA mismatch repair is an essential and highly conserved mechanism to ensure genetic fidelity. The first step in DNA mismatch repair is recognition of DNA base mismatches and insertion or deletions by MutS in bacteria and MSH complexes in eukaryots. The structure for the MSH2-MSH6 complex which recognizes base mismatches and short base insertions has recently become available from crystallography and will be used as the starting point for extensive computational studies to elucidate atomistic details of the mechanism by which mismatch repair is initiated. One aim is to carry out molecular dynamics simulations of MSH2-MSH6 over 100 ns time scales to study allosteric coupling between mismatch recognition and ATPase activity that would lead to conformational changes in MSH2-MSH6 to signal repair initiation. A second aim is to examine the detailed interaction between MSH2-MSH6 and DNA to understand the mechanism by which defective DNA is distinguished from regular DNA by employing biased simulations with a new biasing potential that facilitates translocation of MSH2-MSH6 along DNA. The immediate goal of the development account is to determine the best choice of simulation software and TeraGrid platform in preparation for an MRAC proposal.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 复制后DNA不匹配修复是确保遗传保真度的必不可少且高度保守的机制。 DNA不匹配修复的第一步是对真核生物中细菌和MSH复合物中MUT的DNA碱基不匹配和插入或缺失的识别。 MSH2-MSH6复合物的结构最近从晶体学上获得了识别基础不匹配和短基插入的结构，并将用作广泛的计算研究的起点，以阐明启动不匹配修复的机制的原子性细节。一个目的是在100 ns时间尺度上进行MSH2-MSH6的分子动力学模拟，以研究不匹配识别和ATPase活性之间的变构耦合，这将导致MSH2-MSH6的构象变化以信号修复启动。第二个目的是检查MSH2-MSH6和DNA之间的详细相互作用，以了解通过采用具有新的偏见潜力的偏置模拟来区分有缺陷的DNA与常规DNA区分开的机制，从而促进了MSH2-MSH6沿DNA的易位。开发帐户的直接目标是确定模拟软件和Teragrid平台的最佳选择，以准备MRAC提案。