Abstract: Current x-ray crystallography techniques used to image proteins represent molecules as rigid, single-state structures. While widely used and effective, these techniques fail to account for the molecular dynamics of protein solution states, which can obstruct complete understanding of protein function. Through Kinetic Ensemble Refinement, the molecular motion of protein structures can be captured as they move in solution. We have used Phenix Ensemble Refinement to generate ensemble data for the protein cyclophilin A, an enzyme harboring an important role in protein folding and thus contributing to heart disease, Alzheimer’s disease, and types of cancer. Analysis of ensemble structures of cypA has allowed us to optimize the parameters specified in the phenix grid search script used for ensemble refinement in order to represent the ideal amount of molecular dynamics while maintaining accurate protein structure determination with regards to the deposited crystal data and NMR data for cypA. We have used the molecular visualization program, PyMOL, to compare the multi-state ensemble structures obtained from Phenix, and the molecular dynamics package, Gromacs, to analyze both the structural accuracy and molecular movement displayed by the generated ensemble data. The Kinetic Ensemble approach has strong implications to advance fields such as drug design as a result of more accurate structural determination of solution state protein dynamics.
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