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. In the field of cell signal transduction, molecular structure determinations have provided fundamental structural explanations for the workings of cell signaling pathways. Through its ability to determine structures of signaling proteins in multiple distinct conformations, crystallography has contributed to the structure based understanding of a number of phosphorylation and ligand-activated molecular switches that are an integral component of cell signaling pathways. Dynamic protein motion is a key component of this switching functionality. This project will employ molecular dynamics (MD) to study the molecular details of the conformational transitions that link the different functional states of two classes of cell signaling proteins, protein kinases and nuclear hormone receptors. The goal is a more complete and dynamic understanding of the forces that stabilize the distinct functional states of these proteins and the interconversions between them. Because the timescales of the transitions are long relative to the MD simulation rate, the simulations will investigate novel sampling techniques such as replica-exchange MD and targeted-MD to accelerate simulation times. The computer simulations will be closely coupled to experimental investigations of these proteins currently being carried out in the laboratory
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