ANALYSIS OF PROTEIN STRUCTURAL DIFFERENCES DUE TO GENETIC POLYMORPHISMS

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。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。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。 本研究主要探讨基因多态性对蛋白质三维结构的影响，包括三种方法：（1）通过分子动力学（MD）模拟对特定蛋白质进行直接研究;（2）改进基于规则的多态性对蛋白质结构和稳定性可能产生的有害影响的预测;（3）直观预测引起蛋白质过早截短的多态性的有害影响。对于（1），RBVI/CGL资源，特别是Chimera和图形工作站，正在用于在MD模拟之前进行氨基酸置换（使用Chimera的“swapaa”命令），目视检查模拟产生的结构，并准备出版的图像。对于（2），RBVI/CGL可视化资源（Chimera和图形工作站）被用于检查具有许多此类取代的蛋白质中已知疾病相关氨基酸取代的结构背景，例如过氧化物酶体增殖物激活受体γ，雄激素受体和胰岛素受体，以推导出将特定氨基酸取代与有害结构效应相关的新的一般规则。对于（3），RBVI/CGL资源用于显示疏水表面区域的暴露，可能导致形成有毒聚集体，这是由结构域内的蛋白质截短引起的。对于所有这些项目，在RBVI/CGL AlphaServers上运行的RBVI/CGL MinRMS程序和Chimera的“匹配”命令都用于对齐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.