Lipid-driven alignment and binding of p7 dimers in early oligomer assembly.

Proteins interact with lipid membranes to facilitate important cellular processes that underlie health and disease. Transmembrane proteins like ion channels are often composed of bound monomers forming specific contacts within the bilayer. However, molecular mechanisms of channel assembly are scarce. Understanding the role of lipids in this process may help further explain assembly of oligomeric proteins, which are often clinical drug targets. Using the hepatitis C virus p7 hexamer as a representative of proteins with complex transmembrane topology, this work characterizes early lipid-driven dimerization using molecular dynamics simulations. Comparing dimer interactions in aqueous solution versus on a lipid membrane model reveal that protein-lipid interactions critically guide inter-protein residue alignment and binding. Hydrophobic contacts and hydrogen bonding between key residues and phosphatidylcholine/phosphatidylinositol lipids drive essential helix interactions that promote p7 oligomerization, particularly involving the first helix. This study demonstrates that membrane lipids are essential, dynamic contributors to protein binding and aggregation in cellular membranes.