Molecular dynamics simulations with AMBER have been employed to probe conformational changes in the enzyme dihydrofolate reductase elicited by the binding of its cofactor and various ligands.  MD simulations were conducted with both wild type and trimethoprim-resistant E. coli DHFR on a time scale of 300-350ns. The focus of our investigation has been to understand induced fit and structural changes upon ligand binding through the analysis of three flexible loop regions of DHFR which have been implicated in the regulation of the enzyme's catalytic function. Utilizing MD simulation, we can observe how these flexible loop regions respond to the binding of DHFR's natural substrates and various inhibitors, and thus gain insight into the contributions of each of these flexible loops to DHFR's catalytic function.  Additionally, by monitoring structure changes in response to ligand binding we can further assess and validate the performance of the AMBER protein force fields.

Investigation of induced conformational changes in dihydrofolate reductase

245th National Meeting (2013)

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