标题：Cholesterol and saturated fatty acid stabilize dimerization of helical transmembrane peptides by lowering energy cost related to peptides desolvation from lipids upon dimerization: an insight from atomistic simulation
摘要：Lipids composition of cellular membrane is known to be crucial for regulations of activities of many cells. In immune cells, activities of diverse receptors including T cell receptors and innate immunity receptors are modulated by lipids. In the presence of cholesterol in membranes, saturated fatty acids (FAs) promote formation of ordered lipid microdomain formation and enhance receptor-mediated signaling and inflammation, but the mechanistic detail for the effects of saturated FAs has not been well understood. Here we show that, for a poly-Ile transmembrane (TM) helical peptide, a self-dimerized state is stabilized by about -2.2 kJ/mol by the lipid bilayer of 1:1:1 palmitoyloleoylphosphatidylcholine (POPC)/dipalmitoylphosphatidylcholine (DPPC)/cholesterol compared to a pure dioleoylphosphatidylcholine (DOPC) bilayer in molecular simulations with a united-atom force field. Energy decomposition analysis suggested that the DOPC bilayer has a high Lennard-Jones (LJ) potential energy cost due to non-optimal protein-lipid interactions (poor fitting) upon peptide dimerization relative to the monomers state, but the 1:1:1 bilayer showed a relatively small differential of the protein-lipid LJ potential between the dimer and monomer states. In the 1:1:1 bilayer, both POPC and DPPC resided near the dimerized peptides, with cholesterol mostly residing >3 Å distant from peptides surface. However, a potential energy decomposition analysis did not support the view that peptides segregation from the cholesterol-rich sub-compartment is important for stabilizing the dimerization. Rather, peptide solvation by phospholipids preserved relatively well even after dimerization possibly due to the straightened acyl chains was the key for the dimer stabilization. Taken together, saturated FAs of phospholipids and cholesterol appear to stabilize transmembrane helical peptide dimerization in a sequence-nonspecific manner through the ability of such lipids to indirectly assist peptides solvation by lipids after peptide dimerization.
关键词：protein clustering; protein recruitment; dynamics simulations; GROMOS; lipid rafts
