Abstract
Energetics of protein side chain partitioning between aqueous solution and cellular membranes is of fundamental importance for correctly capturing the membrane binding and specific protein-lipid interactions of peripheral membrane proteins. We recently reported a highly mobile membrane mimetic (HMMM) model that accelerates lipid dynamics by modeling the membrane interior partially as a fluid organic solvent while retaining a literal description of the lipid head groups and the beginning of the tails. While the HMMM has been successfully applied to study spontaneous insertion of a number of peripheral proteins into membranes, a quantitative characterization of the energetics of membrane-protein interactions in HMMM membranes has not been performed. We report here the free energy profiles for partitioning of 10 protein side chain analogues into a HMMM membrane. In the interfacial and headgroup regions of the membrane, the side chain free energy profiles show excellent agreement with profiles previously reported for conventional membranes with full-tail lipids. In regions where the organic solvent is prevalent, the increased dipole and fluidity of the solvent generally result in a less accurate description, most notably overstabilization of aromatic and polar amino acids. As an additional measure of the ability of the HMMM model to describe membrane-protein interactions, the water-to-membrane interface transfer energies were analyzed and found to be in agreement with the previously reported experimental and computational hydrophobicity scales. We discuss strengths and weaknesses of HMMM in describing protein-membrane interactions as well as further development of model membranes.