MODULATING STRUCTURE AND DYNAMICS AT ALLOSTERIC SITES USING SMALL MOLECULES

使用小分子调节变构位点的结构和动力学

• 批准号: 7955514
• 负责人: MATTHEW P JACOBSON
• 金额: $ 0.89万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7955514
• 关键词: Allosteric Site; Binding; Computer Retrieval of Information on Scientific Projects Database; Coupled; Cysteine; Funding; Grant; Imagery; Informatics; Institution; Methods; Motion; Physics; Proteins; Research; Research Personnel; Resources; Sampling; Site; Source; Structure; Torsion; United States National Institutes of Health; base; biocomputing; flexibility; molecular dynamics; molecular mechanics; small molecule

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. Allosteric sites have shown great potential for selective inhibition of particular protein targets but limited exploration. Such sites are difficult to target with small molecules because they are highly flexible, and because binding may not be sufficient to cause the desired effect. I am developing a molecular dynamics analysis method to search for correlated motions to identify allosteric sites and allosteric networks of coupled residues. I am also developing an all-atoms, physics-based torsion-angle sampling molecular mechanics approach to predict bound geometries of cysteine-conjugating compounds and am studying the allosteric effects of these covalent compounds using molecular dynamics.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 变构位点已经显示出选择性抑制特定蛋白质靶点的巨大潜力，但探索有限。这些位点难以用小分子靶向，因为它们是高度柔性的，并且因为结合可能不足以引起期望的效果。我正在开发一种分子动力学分析方法来寻找相关的运动，以确定耦合残基的变构位点和变构网络。我还开发了一个全原子，基于物理学的扭转角采样分子力学方法来预测半胱氨酸共轭化合物的束缚几何形状，并使用分子动力学研究这些共价化合物的变构效应。