Molecular Dynamics Simulations and Free Energy Calculations on the Enzyme 4-Hydroxyphenylpyruvate Dioxygenase

4-Hydroxyphenylpyruvate dioxygenase is a relevant target in both pharmaceutical and agricultural research. We report on molecular dynamics simulations and free energy calculations on this enzyme, in complex with 12 inhibitors for which experimental affinities were determined. We applied the thermodynamic integration approach and the more efficient one-step perturbation. Even though simulations seem well converged and both methods show excellent agreement between them, the correlation with the experimental values remains poor. We investigate the effect of slight modifications on the charge distribution of these highly conjugated systems and find that accurate models can be obtained when using improved force field parameters. This study gives insight into the applicability of free energy methods and current limitations in force field parameterization. (C) 2011 Wiley Periodicals, Inc. J Comput Chem 32: 2160-2169, 2011