(587c) Lipid-Mediated Protein-Protein Interactions: Modeling the Formation of Hepatitis C Virus p7 Dimers

Hepatitis C virus (HCV) morphogenesis requires the interplay of viral proteins and lipids at the endoplasmic reticulum (ER). Changes in both protein structural assemblies and lipid distribution occurs at the cell membrane interface, leading to remodeling of the local lipid environment in preparation for new viral particles. These changes result in different mechanical and physical properties in the local membrane environment. The p7 protein from HCV is a viroporin that holds promising yet unexplored therapeutic targets; its molecular mechanism of formation in the ER remains unclear. Protein-induced changes to the local membrane environment have repercussions in lipid homeostasis and fat storage. Similarly, lipid-lipid interactions modulate interactions among p7 monomers. Our previous work examined the effect of membrane lipid composition on the insertion of a single p7 monomer using molecular dynamics (MD) simulations. Deeper peptide insertion was observed in the presence of phosphatidylserine (PS) lipids, which enabled stronger electrostatic and hydrophobic interactions with the first two helices of the protein. Here, we probed lipid-lipid interactions that facilitate dimerization of p7 peptides. Using a dimer from the available channel coordinates as a starting point (PDBID 2M6X), we compared protein-protein interactions and structure (i) in water and (ii) at the membrane surface. Preliminary analysis shows the C-terminus of one monomer interacts indistinctly with multiple lipid species, while the N-terminus of another prefers contacts with phosphatidylcholine (PC) lipids to enable proper positioning between the dimers. Nonetheless, the dimers in these simulations are not stable; current work will serve as a baseline to use enhanced sampling simulations to explore additional protein-protein conformations and propose a mechanism of dimer formation en-route to the assembly of a p7 channel. This work highlights the role of membrane lipids in facilitating protein-protein interactions on the cell membrane surface and their posterior insertion using the p7 viroporin from HCV as a case study.