QM/MM study of the mechanism of reduction of 3-hydroxy-3-methylglutaryl coenzyme A catalyzed by human HMG-CoA reductase
Detailing with atomistic resolution the reaction mechanism of human HMG-CoA reductase (HMG-CoA-R) might provide valuable insights for the development of new cholesterol-lowering drugs. In the pursuit of that goal we developed three molecular models of human HMG-CoA-R with different active site protonation states and employed molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) calculations to detail the first reduction step, the rate-limiting step, of HMG-CoA-R. Our results predict an active site with a neutral glutamate (Glu559) as the most catalytically competent structure. The favored reaction pathway suggests the formation of a mevaldyl-CoA intermediate protonated by a conserved active site lysine (Lys691), corroborating previous site-directed mutagenesis studies. The conserved active site glutamate and aspartate residues (Glu559 and Asp767), along with the ribose moiety of NADPH, form a hydrogen bond network crucial to the increase of the stabilizing effect of Lys691 over the transition state.