HMG-CoA reductase catalyzes the four-electron reduction of HMG-CoA to mevalonate and is of considerable biomedical relevance because of the impact of its statin inhibitors on public health. Theozyme quantum mechanical (QM) and full protein quantum mechanical/molecular mechanical (QM/MM) calculations up to the B3LYP/6-31g(d,p)//B3LYP/6-311++g(2d,2p) level of theory were employed to generate an atomistic description of the enzymatic reaction process and its energy profile. These models predict that the catalytically important Glu83 is protonated prior to hydride transfer and that it acts as the general acid or base throughout the reaction. With Glu83 protonated, the activation energies calculated for the sequential hydride transfer reactions, 21.8 and 19.3 kcal/mol, respectively, are in qualitative agreement with the experimentally determined rate constant for the entire reaction. Lys267 is critical for stabilization of the transition state in forming an oxyanion hole with the protonated Glu83. To study the reaction in a dynamic context, force fields were generated for the reactant, transition state, and product of each hydride transfer reaction using the quantum guided molecular mechanics (Q2MM) method. The Q2MM generated force field treats the transition state as a minimum on the potential energy surface so standard molecular dynamics programs can be used to generate an ensemble of transition state structures. Structural elements, hessian elements, and relative energies derived from the theozyme and QM/MM calculations were used to fit new parameters through minimization of a penalty function. The force fields generally are able to reproduce the QM geometries very well with RMSD values <0.1� and there is adequate agreement between the QM and MM hessian elements. Structural comparison between QM/MM calculations and available crystal structures along with a comparison between the MM and QM/MM energies of selected snapshots from a molecular dynamics simulation will serve as validation of the force fields.

Mechanism of HMG-CoA reductase and the development of quantum mechanically trained force fields for the reaction

246th National Meeting (2013)

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