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.
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