Computational study on the activity of serum Paraoxonase-1 (PON1) in lipid membrane with Glutamine/Arginine polymorphism at position 192

Abstract

Serum Paraoxonase-1(PON1) is a calcium dependent hydrolytic enzyme that is closely associated with high-density lipoprotein (HDL). This enzyme contains a promiscuous active site that could undergo three different types of catalytic activities such as organophosphatase activity, lactonase activity and arylesterase activity. Among these polymorphisms in serum PON1, the Glutamine/Arginine polymorphisms at position 192 are prominent and have a large impact on the rate of the catalytic activities of serum PON1. The main objectives of this study were to model the PON1 protein in a phospholipid bilayer and to investigate the possible mechanism for the change in catalytic activity of serum PON1 due to Q192R polymorphism. The lipid-bound PON1 protein was modeled using the CHARMM-GUI web server. The diazoxon ligand is a well-known organophosphate that was found to have a higher hydrolytic activity in R192 isoform than in Q192 isoform and is used as the ligand for this investigation. This ligand was docked to the serum PON1 isoforms by AutoDock Vina. Best docking poses were then subjected to molecular dynamics simulation for 200 ns using Amber 16 software. The structural analysis of output trajectories and docking results indicate that diazoxon ligand is more stable in R192 isoform than Q192 isoform which could be a reason for the greater activity of R192 isoform. Further studies will be carried out to investigate the effect of polymorphisms on the activities of PON1 protein using the developed model.