realistic-membrane-modeling-using-complex-lipid-mixtures-simulation

Realistic Membrane Modeling Using Complex Lipid Mixtures in Simulation Studies

Lipids are structural building blocks of cell membranes; lipid species vary across cell organelles and across organisms. This variety results in different ...

State University of New York at Buffalo

The mammalian cell membrane consists of thousands of different lipid species, and this variety is critical for biological function. Alterations to this balance can be dangerous as they can lead to permanent disruption of lipid metabolism, a hallmark in several viral diseases. The Flaviviridae family is made up of positive single-stranded RNA viruses that assemble at or near the location of lipid droplet formation in the endoplasmic reticulum. These viruses are known to interfere with lipid metabolism during the onset of liver disease, albeit to different extents. Pathogenesis of these infections involves specific protein-lipid interactions that alter lipid sorting and metabolism to sustain propagation of the viral infection. Recent experimental studies identify a correlation between viral proteins and lipid content or location in the cell, but these do not assess membrane-embedded interactions. Molecular modeling, specifically molecular dynamics simulations, can provide molecular-level spatial and temporal resolution for characterization of biomolecular interactions. This review focuses on recent advancements and current knowledge gaps in the molecular mechanisms of lipid-mediated liver disease preceded by viral infection. We discuss three viruses from the Flaviviridae family: dengue, zika, and hepatitis C, with a particular focus on lipid interactions with their respective ion channels, known as viroporins.

Protein-driven membrane remodeling: Molecular perspectives from Flaviviridae infections.

Viral proteins interact with lipid membranes during various stages in the viral life cycle to propagate infection. p7 is an ion channel forming protein of Hepatitis C virus (HCV) that participates in viral assembly. Studies show that it has close ties to lipid metabolism in the cell and anionic phosphatidylserine (PS) lipids are suggested to be key for its permeabilizing function, but the mechanism of its interaction with the lipid environment is largely unknown. To begin unraveling the molecular processes of the protein, we evaluated the impact of lipid environment on the binding and insertion mechanism of p7 prior to channel formation and viral assembly using molecular dynamics simulations. It is seen that p7 is sensitive to its lipid environment and results in different remodeling patterns in membranes. Helix 1 (H1) is especially important for peptide insertion, with deeper entry taking place when the membrane contains phosphatidylserine (PS). Helix 2 (H2) and the adjacent loop connecting to Helix 3 (H3) prompts recruitment of phosphatidylethanolamine (PE) lipids to the protein binding site in membrane models with lower surface charge. This work provides perspectives on the interplay between protein-lipid dynamics and membrane composition, and insights on membrane reorganization in mechanisms of disease.

Viviana Monje-Galvan

Department of Chemical and Biological Engineering

State University of New York at Buffalo

Realistic Membrane Modeling Using Complex Lipid Mixtures in Simulation Studies

Viviana Monje-Galvan

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Chemical and Biological Engineering

State University of New York at Buffalo

Realistic Membrane Modeling Using Complex Lipid Mixtures in Simulation Studies

Department of Chemical and Biological Engineering