Molecular dynamics simulations and free energy calculations on the enzyme 4‐hydroxyphenylpyruvate dioxygenase

Abstract

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.

Free Energy Methods in Drug Design: Prospects of “Alchemical Perturbation” in Medicinal Chemistry

“…We do not cover applications of implicit models such as the generalized Born solvent model. Alchemical free energy methods have also been employed in protein mutation studies, − where one residue is alchemically transformed to another, to determine what biological effect this would have, and variations on these methods have been successful in a medicinal chemistry context. , Further, one-step perturbation methods where the kinetic and potential energies of the system are not expressed as a function of λ have also demonstrated moderate to high success. , Monte Carlo methods can be used to sample the molecular structures rather than MD. − Finally, we do not discuss quantum mechanical methods, which are arguably more accurate than molecular mechanics-based MD, but they are even slower to compute due to the increased complexity involved. − …”

Free energy calculations elucidate substrate binding, gating mechanism, and tolerance‐promoting mutations in herbicide target 4‐hydroxyphenylpyruvate dioxygenase

“…The Amber99SB‐ILDN force field was used for the protein description and the TIP3P model for the water molecules. The Fe 2+ ion was described as a single, doubly charged van der Waals particle following a strategy used in earlier work . The GAFF force field was used to describe the HPP and the HGA molecule.…”

“…The Fe 2+ ion was described as a single, doubly charged van der Waals particle following a strategy used in earlier work. 26 The GAFF force field 27 was used to describe the HPP and the HGA molecule. Force field parameters for HPP and HGA were determined with ANTECHAMBER 28 via the acpype interface.…”

Pyranose Dehydrogenase Ligand Promiscuity: A Generalized Approach to Simulate Monosaccharide Solvation, Binding, and Product Formation

“…One can easily show that expressing the ensemble average for reference compound R1 of equation (1 ) as an umbrella-weighted ensemble, calculated from a simulation of reference state R2 using equation (6 ), can be expressed as where both terms on the right-hand side are readily calculated from the simulation of R2. This way, simulations of the three reference states lead to three estimates of , which can be exponentially averaged to obtain where the overbar indicates an average over three values of i [52] . Statistical error estimates for the individual ensemble averages used in equation (1 ) were obtained from covariances and the statistical inefficiency as described in [53] .…”