Conserved recognition and divergent peripheral dynamics of designed statin analogues at human HMG-CoA reductase: ensemble docking and replicated molecular dynamics

Human 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) recognizes statins through a conserved polar binding region, while peripheral chemical differences may alter protein–ligand dynamics. We docked 13 chemically defined statin-related molecular states across six ligand-bound HMGCR crystal structures using three independent searches per state–receptor combination (234 searches). Eight selected states were then evaluated in three independently seeded 50 ns molecular dynamics (MD) simulations each (24 trajectories; 1.2 μs total). Protein-aligned root-mean-square displacement (RMSD) was analyzed for the entire ligand, a conserved nine-heavy-atom hydroxy-acid motif, and the complementary peripheral atoms, together with residue-level contacts. Top-ranked motif-compatible pose recovery varied between receptor structures, from 15/39 searches for 1HW8 to 38/39 for 1HWK. The G3-001 stereoisomers differed substantially in the persistence of geometric hydrogen-bond criteria involving HMGCR Glu559: median replica occupancies were 8.2% for G3-001 A (R) and 91.0% for G3-001 B (S), with higher occupancy for B in each of the three paired replica comparisons. A separate ether-chain extension (G3-005) exhibited pronounced peripheral displacement in one replica while selected recognition-site proximities remained. These computational observations identify testable relationships among receptor conformation, ligand stereochemistry, and interaction persistence.