MISMATCH RECOGNITION BY MSH2-MSH6

MSH2-MSH6 的不匹配识别

• 批准号: 8171881
• 负责人: Michael Feig
• 金额: $ 0.11万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171881
• 关键词: ATP phosphohydrolase; Accounting; Bacteria; Complex; Computer Retrieval of Information on Scientific Projects Database; Coupling; Crystallography; DNA; DNA biosynthesis; Development; Ensure; Funding; Genetic; Goals; Grant; 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; simulation software

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 复制后 DNA 错配修复是确保遗传保真度的重要且高度保守的机制。 DNA 错配修复的第一步是通过细菌中的 MutS 和真核生物中的 MSH 复合体识别 DNA 碱基错配和插入或删除。识别碱基错配和短碱基插入的 MSH2-MSH6 复合物的结构最近已从晶体学中获得，并将用作广泛计算研究的起点，以阐明启动错配修复机制的原子细节。目标之一是在 100 ns 时间尺度上对 MSH2-MSH6 进行分子动力学模拟，以研究错配识别和 ATP 酶活性之间的变构耦合，这将导致 MSH2-MSH6 的构象变化以发出修复启动信号。第二个目标是检查 MSH2-MSH6 和 DNA 之间的详细相互作用，以了解通过采用有偏差的模拟来区分缺陷 DNA 和常规 DNA 的机制，该模拟具有新的偏置电位，可促进 MSH2-MSH6 沿着 DNA 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，为 MRAC 提案做准备。