MODULATING STRUCTURE AND DYNAMICS AT ALLOSTERIC SITES USING SMALL MOLECULES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 变构位点在选择性抑制特定蛋白质靶点方面显示出巨大的潜力，但探索有限。这些位点很难与小分子结合，因为它们具有高度的灵活性，而且结合可能不足以产生预期的效果。我正在开发一种分子动力学分析方法来寻找相关的运动，以确定偶联残基的变构位置和变构网络。我还在开发一种基于物理的全原子扭转角度采样分子力学方法来预测半胱氨酸共轭化合物的结合几何，并使用分子动力学研究这些共价化合物的变构效应。

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.