Planar Stacking Interactions in the Binding of Type II Statins to HMG-CoA Reductase

Statins act by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and thereby reducing cholesterol synthesis. Statins can be divided into two classes based on their structure; Type I statins (e.g., simvastatin) exhibit binding via a decalin ring structure, while type II statins (e.g., rosuvastatin) exhibit additional binding via their fluorophenyl group [1]. Statins primarily use dipole/dipole and hydrogen bonds to bind to the active site of the reductase, focusing on the portion of the active site dominated by lysine 735, arginine 590, aspartic acid 690, serine 684, lysine 691, asparagine 755, lysine 692 and glutamine 559 with minimal explicit incorporation of hydrophobic side-chain interactions [2] (1HW8, 1HW9, 1HWJ, 1HWI, 1HWK, 1HWL).We examine potentially important enzyme-ligand interactions currently not incorporated: planar stacking interactions between type II statins and residue arginine 590 in the HMG-CoA reductase active site. We calculated electronic interaction energies between the residue and types of statins using M06/6-311++G** level in the gas phase. The results indicate the absolute binding energy for type II statins is more overall than type I statins. In addition, stacking interaction is verified through AIM calculations at MP2/6-31G(0.25)* level.