ANALYSIS OF PROTEIN STRUCTURAL DIFFERENCES DUE TO GENETIC POLYMORPHISMS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。本项目探讨了导致疾病相关蛋白序列变化的遗传多态性对蛋白质三维（3D）结构的影响，采用三种方法：(1)通过分子动力学（MD）模拟对选定蛋白进行直接研究；(2)改进了基于规则的预测多态性对蛋白质结构和稳定性可能产生的有害影响；(3)对导致蛋白质过早截断的多态性的有害影响进行视觉预测。对于(1)，RBVI/CGL资源，特别是Chimera和图形工作站，正在用于在MD模拟之前执行氨基酸替换（使用Chimera的“swapaa”命令），以直观地检查模拟产生的结构，并准备发布图像。对于(2)，RBVI/CGL可视化资源（Chimera和图形工作站）被用于检查蛋白质中已知与疾病相关的氨基酸取代的结构背景，例如过氧化物酶体增殖体激活受体γ、雄激素受体和胰岛素受体，以便得出特定氨基酸取代与有害结构效应相关的新一般规则。对于(3)，RBVI/CGL资源被用于可视化暴露的疏水表面积，可能导致形成有毒聚集体，由结构域内的蛋白质截断引起。对于所有这些项目，在RBVI/CGL alphaserver上运行的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.