Molecular dynamics simulations of Hepatitis C viroporin and lipid membranes.

Abstract

Mammalian cell membranes contain thousands of different lipid species with important roles in cellular processes that involve interactions with proteins. Disruption of lipid metabolism is deleterious to the cell and a hallmark of viral infections. One factor that causes this is the interactions of uniquely structured viral proteins with membrane lipids during virus morphogenesis. These interactions drive distinct protein and lipid interactions that aid virus propagation and modify the local membrane environment. Hepatitis C virus (HCV) is notorious for causing fat mismanagement in the liver, that can often develop into non-alcoholic fatty liver diseases (NAFLDs). These can progress to more severe conditions such as cirrhosis and hepatic carcinoma. p7 is a non-structural HCV protein critical for virus assembly in the endoplasmic reticulum, close to sites of lipid droplet formation. We hypothesize that p7 induces local changes in membrane composition that may lead to lipid droplets with different characteristics in lipid composition and structural properties, which contribute to fat mismanagement in the long run. As a first step, all-atom molecular dynamics were run to examine interactions between a p7 monomer and model lipid bilayers. This study aims to determine differences in protein-lipid interactions in membrane models with different lipid composition, and to quantify membrane response to protein binding. Specifically, we characterize protein binding time and conformation, frequency of contact between specific amino acids and lipid species, and changes to the local membrane environment from a total of over 7us of simulation trajectories. Protein residues in the N-terminus consistently come in contact with the bilayer first, and a more charged membrane surface results in a flatter protein bound conformation that allows for partial protein insertion.