Effect of pH on structural dynamics of HMG-CoA reductase and binding affinity to β-sitosterol.

Human 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR; EC 1.1.1.34) catalyzes the conversion of (3S)-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonic acid, which has been defined as the rate-limiting step in the synthesis of cholesterol and other isoprenoids, thus playing a critical role in cellular cholesterol homeostasis. In this study, the effect of changing pH on the structural dynamics and binding affinity of HMGCR were investigated by molecular dynamics simulation using OpenMM, and molecular docking using Autodock Vina. The results pinpoint pH 8.0 for optimum structural stability/activity of HMGCR, and the insightful relationships between pH, structural dynamics radius of gyration (Rg) or root mean square deviation (RMSD), and binding affinity of HMGCR. This method will be useful to predict the pH for the uncharacterized human proteins, toward biomedical and biotechnological applicationsCommunicated by Ramaswamy H. Sarma.