Structure, dynamics, and catalytic function of dihydrofolate reductase

Molecular motions are widely regarded as contributing factors in many aspects of protein function. The enzyme dihydrofolate reductase (DHFR), and particularly that from Escherichia coli, has become an important system for investigating the linkage between protein dynamics and catalytic function, both because of the location and timescales of the motions observed and because of the availability of a large amount of structural and mechanistic data that provides a detailed context within which the motions can be interpreted. Changes in protein dynamics in response to ligand binding, conformational change, and mutagenesis have been probed using numerous experimental and theoretical approaches, including X-ray crystallography, fluorescence, nuclear magnetic resonance (NMR), molecular dynamics simulations, and hybrid quantum/classical dynamics methods. These studies provide a detailed map of changes in conformation and dynamics throughout the catalytic cycle of DHFR and give new insights into the role of protein motions in the catalytic activity of this enzyme.