Interaction of Snare Mimetic Peptides with Lipid Bilayers

Abstract

The coiled-coil forming peptides, ‘K’ (KIAALKE)3 and ‘E’ (EIAALEK)3 represent a minimal model for the action of SNARE proteins. Their action on the membrane is typically pictured as a zipper-like closing of the coiled-coil, bringing the membranes into close proximity. However, the individual peptides are significantly less ordered in solution and peptide K has been shown to interact with the membrane. Thus, the real coiled-coil assembly process is likely to be less straightforward and will possess different free energy contributions related to helix folding, coiled-coil assembly and competing interactions with the membrane. To investigate these different factors, we perform molecular simulations and free energy calculations. We use all atom simulations to characterize the interactions of the peptides with lipid bilayers and to analyze the effect of bilayer composition, peptide secondary structure, and the presence of additional residues often found at the peptide terminals. The potentials of mean force (PMF) for bringing the peptides to the bilayer surface are calculated for two bilayer compositions used experimentally: A neutral bilayer containing bulky PC head-groups, and a charged bilayer containing PG lipids. The PMF profiles show minima for the interactions with the PG bilayers, whereas the bulkier PC head groups present a considerable barrier for embedding the peptide in the membrane, and the results are strongly dependent on the peptide secondary structure. To clarify the different free energy contributions to coiled-coil formation, a series of Metadynamics simulations are conducted which analyze the stability of the alpha helical structure in solution, close to the bilayer and in the folded coiled coil. The energy contributions obtained from these all atom simulations can be used to obtain an optimized coarse grained-model for membrane fusion.