How Lipid and Water Physical Chemistry May Control Fusion: Behavior of Membrane Interfaces and Fusion Peptides

Abstract

Membrane fusion is an essential process in infection by enveloped viruses, synaptic exocytosis, and vesicle trafficking. As interacting membranes are brought together prior to fusion, the resulting membrane-water-membrane interface has surprising and non-bulk-like properties. Here we ask two questions regarding this membrane-membrane interface: how does the physical chemistry differ from bulk, and how do fusion peptides affect this interface. We have used atomistic molecular dynamics simulation to study these interfacial behavior at high resolution. At vesicle-vesicle interfaces prior to fusion, we observe in our simulations a distinct ordering of water between the two membranes and a concomitant slowing of dynamics. We used committor analysis to examine the role of fine water structure in fusion; holding the vesicles fixed while resampling water conformations from a solvent box substantially speeds fusion dynamics, with a small but significant effect on fusion energetics. These slowed dynamics may provide another reason for the reported propensity of fusion stalks to form around the periphery of a contact interface.We have also examined the effect of influenza fusion peptides in bilayers and at membrane interfaces. We and others have previously hypothesized that lipid tail protrusion is a precursor to fusion stalk formation. In our simulations, influenza fusion peptides promote tail protrusion most strongly in a kinked helix conformation with the ends inserted into the hydrophobic layer. Straight helix and helical hairpin conformations occupying an interfacial position promote tail protrusion less strongly.