ENERGETICS OF THE CLEFT CLOSING TRANSITION AND GLUTAMATE BINDING IN THE GLUTAMA

谷氨酸中裂隙闭合转变和谷氨酸结合的能量

• 批准号: 7956194
• 负责人: MARIA G KURNIKOVA
• 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/7956194
• 关键词: Adopted; Binding; Biomedical Research; Cleaved cell; Computer Retrieval of Information on Scientific Projects Database; Computing Methodologies; Electrostatics; Environment; Free Energy; Funding; Glutamates; Grant; High Performance Computing; Institution; Ligands; Modeling; Molecular Conformation; Mutate; Mutation; Pathway interactions; Proteins; Research; Research Personnel; Resources; Running; Sampling; Source; Structure; Thermodynamics; United States National Institutes of Health; mutant; 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. By running MD simulations, we demonstrated that GluR2 adopts the open form. To estimate the free energy differences between two conformations we used the pathway of the opening transition as has been determined in our previous study. We employed the combined approach, which includes Thermodynamics integration (TI) in which the protein is mutated in one conformation and Umbrella Sampling (US), along the pathway of the opening transition as has been determined in our previous study. To get the free energy profile from the closed to the open form we kept the closed conformation in the absence of ligand with harmonic constrains during mutation the E705 residue to E705-0.75. Then umbrella sampling MD simulations were performed to determine free energy of the structural transition from the closed to open structure for GluR2 with the E705-0.75 mutant. Next the open GluR2 with E705-0.75 was mutated to E705 to adopt its previous electrostatic environment. A combination of computational methods has been employed here to model the opening transition and compute the free energy differences using a thermodynamic cycle

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。 通过运行MD模拟，我们证明Glur2采用了开放形式。为了估计两种构象之间的自由能差，我们使用了开场过渡的途径，就像我们先前的研究中所确定的那样。我们采用了组合方法，其中包括热力学整合（Ti），其中蛋白质以一种构象和雨伞采样（US）突变（US），正如我们先前的研究所确定的那样。为了从封闭形式获得自由能曲线，在突变期间没有谐波约束的情况下，我们保持了闭合构象，E705残基将E705-0.75保持在E705残基。然后进行伞采样的MD模拟，以确定从闭合到开放结构的结构过渡的自由能，该结构使用E705-0.75突变体进行了GLUR2的开放结构。接下来，将E705-0.75的开放式GLUR2突变为E705，以采用以前的静电环境。这里已经采用了计算方法的组合来建模开放过渡并使用热力学循环计算自由能差