Lipid-Driven Alignment and Binding of p7 Dimers in Early Oligomer Assembly.

Proteins engage in interactions with lipid membranes to facilitate important cellular processes that form the basis of healthy or sick biological conditions. Transmembrane proteins such as ion channels are often made up of bound monomers that engage in specific contacts within the bilayer. However, molecular mechanistic information related to how these channel structures form is scarce. Understanding the role of lipids in driving this process have the potential to close knowledge gaps regarding the assembly behavior of oligomeric proteins which are often clinical targets for disease treatment. Using the hepatitis C virus p7 hexamer as a case study, this work focuses on characterizing the interactions that dictate the beginnings of dimerization using molecular dynamics simulations. Results comparing dimers formed in aqueous solution to those at the surface of a lipid membrane model reveal that protein-lipid interactions are critical in aiding the proper alignment and binding of inter-protein residues. Hydrophobic protein-lipid interactions and hydrogen bonding of key residues to phosphatidylcholine and phosphatidylinositol membrane lipids drive the characteristic inter-protein helix interactions that underlie p7 oligomerization. This increases favorable binding between hydrophobic protein residues, particularly for the first helix of the p7 monomers. This study provides evidence that membrane lipids are a necessary and dynamic factor that contributes to appropriate binding and association of proteins for channel formation within cellular membranes.