Computational Studies on the Mechanism of HMG-CoA Reductase and the Grignard SRN1 Reaction

HMG-CoA reductase catalyzes the four-electron reduction of HMG-CoA to mevalonate in the biosynthetic pathway for cholesterol. The enzyme is of considerable biomedical relevance because of the public health impact of its inhibitors called statins that are prescribed to control cholesterol levels and reduce the risks associated with coronary heart disease. Surprisingly, the level of mechanistic understanding of the complex reaction mechanism of HMG-CoA reductase is not commensurate with its importance. The combination of x-ray crystallography and computational methods, such as theozyme and QM/MM models, has allowed a more detailed understanding of the mechanism for the reaction. The models predict that the catalytic residue, Glu83, is protonated prior to the reaction, and the resulting activation energies estimated for the sequential hydride transfer reactions, 21.8 and 19.3 kcal/mol, are in agreement with the experimentally determined rate constant.

In addition to the QM/MM models for the reaction, quantum-guided molecular mechanics (Q2MM) transition state force fields (TSFF) were developed. The TSFFs are not only four orders of magnitude faster than QM/MM dynamics and therefore allow for more complete sampling of the protein motions during the reaction, but also address the problem of the boundary region inherent to all QM/MM methods by permitting a simulation at a consistent level. Good agreement is observed structurally between the previously mentioned QM/MM models and the Q2MM TSFF models. In addition, molecular dynamics simulations with the Q2MM TSFFs are stable on relatively long time scales, ~10 ns, and are useful for producing an ensemble of transition structures to describe the reaction.

The cross-coupling of sp² centers is an important process for the synthesis of biaryl groups. Hayashi and coworkers recently reported a transition metal-free method for coupling easily accessible aryl Grignard reagents and aryl iodides. The reaction involves a single electron transfer and was originally classified as a nucleophilic radical substitution (SRN1) reaction until radical clock experiments suggested that there is no radical intermediate. DFT calculations predict the formation of an Mg-radical ion pair that reacts towards products faster than the rate of the radical clock reaction. Based on these results a novel variation of the SRN1 mechanism is proposed for this reaction that is consistent with the available experimental results.