ANALYSIS OF PROTEIN STRUCTURAL DIFFERENCES DUE TO GENETIC POLYMORPHISMS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。本项目使用三种方法探索引起疾病相关蛋白质序列变化的遗传多态对蛋白质三维(3D)结构的影响：(1)通过分子动力学(MD)模拟对选定的蛋白质进行直接研究；(2)改进基于规则的多态对蛋白质结构和稳定性的可能有害影响的预测；(3)视觉预测多态导致蛋白质过早截断的有害影响。对于(1)，RBVI/CGL资源，特别是Chimera和图形工作站，正被用于在MD模拟之前进行氨基酸替换(使用Chimera的“swapaa”命令)，以目视检查模拟产生的结构，并准备用于出版的图像。对于(2)，正在使用RBVI/CGL可视化资源(嵌合体和图形工作站)来检查具有许多这样的替换的蛋白质中已知的与疾病相关的氨基酸替换的结构背景，例如过氧化体增殖物激活的受体伽马、雄激素受体和胰岛素受体，以便得出将特定的氨基酸替换与有害的结构效应联系起来的新的一般规则。对于(3)，RBVI/CGL资源正被用于可视化疏水表面积的暴露，可能导致由于结构域内的蛋白质截断而导致的有毒聚集体的形成。对于所有这些项目，运行在RBVI/CGL AlphaServer上的RBVI/CGL MinRMS程序和Chimera的“Match”命令用于对齐3D结构。

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. This project explores the effects on protein three-dimensional (3D) structure of genetic polymorphisms causing sequence changes in disease-related proteins, using three approaches: (1) direct investigation via molecular dynamics (MD) simulations on selected proteins; (2) improvement of rule-based prediction of polymorphisms' likely deleterious effects on protein structure and stability; (3) visual prediction of deleterious effects of polymorphisms causing premature truncations of proteins. For (1), RBVI/CGL resources, particularly Chimera and the graphics workstations, are being used to perform amino acid substitutions prior to MD simulations (using Chimera's "swapaa" command), to visually inspect structures resulting from the simulations, and to prepare images for publication. For (2), RBVI/CGL visualization resources (Chimera and the graphics workstations) are being used to inspect the structural contexts of known disease-related amino acid substitutions in proteins with many such substitutions, such as peroxisome proliferator-activated receptor gamma, the androgen receptor, and the insulin receptor, in order to derive new general rules relating specific amino acid substitutions to deleterious structural effects. For (3), RBVI/CGL resources are being used for visualization of exposure of hydrophobic surface area, possibly leading to formation of toxic aggregates, caused by protein truncations within structural domains. For all of these projects, the RBVI/CGL MinRMS program, run on the RBVI/CGL AlphaServers, and Chimera's "match" command are used to align 3D structures.