Molecular dynamics simulation to investigate Glutamine/Arginine polymorphism at position 192 of serum paraoxonase-1(PON1)

Abstract

Serum Paraoxonase-1(PON1) is a hydrolytic enzyme which is closely associated with High-density lipoprotein (HDL). Even though recent studies have shown that these polymorphisms can cause the lowering of the activity of this enzyme, the mechanism of protein–HDL interaction is not clearly understood. Thus, this study was mainly focused on investigating the structural changes associated with Glutamine/Arginine polymorphisms at position 192 using molecular dynamics (MD) simulations. Accordingly, our main objectives were to model PON1 in lipid bilayer to understand the correct orientation and to identify the structural changes of the protein due to the polymorphism at position 192 using MD snapshots. The CHARMM GUI web server was used to model complexes with PON1 and lipid bilayer and 200 ns MD run was performed using AMBER 16 software. One lipid-unbound and three lipid-bound systems were investigated. Seven different substrates were docked to understand the different activities of the enzyme. Out of them 7-odiethylphosphoryl- 3-cyano-7-hydroxycoumarin (DepCyc) showed the highest binding affinity. The binding pockets of lipid-bound Q192 and R192 were observed to be larger than that of lipid-bound K192. This difference in the volume of binding pockets allowed the substrate selectivity of the enzyme.