Molecular dynamics study of the interaction between nitrosamines and plasma PAF-AH protein coupled to liposomal membrane

Abstract

Nitrosamines are compounds classified as emerging contaminants, carcinogens, and oxidants. They can alter cell membrane properties and induce an increase in biologically active lipids, such as arachidonic acid and PAF, a potent pro-inflammatory agent capable of inducing the onset of liver and inflammatory diseases. Lp-PLA2 (alternatively known as platelet-activating factor-acetylhydrolase - PAF-AH) is an enzyme that catalyzes the hydrolysis of PAF and belongs to the PLA2 superfamily, it is structurally associated with plasma lipoprotein HDL. Since Lp-PLA2 hydrolyzes PAF into its inactive form (lyso-PAF), Lp-PLA2 levels are proposed to be determined by in vivo levels of PAF and may thus serve as markers for PAF. By catabolizing PAF, Lp-PLA2 appears to play an anti-inflammatory role. In this work, we will use two nitrosamines (N-Nitrosodiethylamine and N-Nitrosodimethylamine) to perform molecular dynamics studies that will be carried out in the BioSIM laboratory (University of Porto) to evaluate the molecular interaction of these nitrosamines on the Lp-PLA2 protein, on the lipid membrane and on the Lp-PLA2 protein interaction interface. This biochemical and biophysical evaluation will be performed using AMBER software to identify the structural behavior of the protein and the coupled complexes. These simulations will be performed by inserting the proteins into a heterogeneous lipid bilayer model, representative of the human plasma membrane, with an appropriate distribution of the different lipid components. (AU)