标题：Why have cholesterol and saturated fatty acids acquired proinflammatory roles during evolution? – A hypothesis from atomistic simulations showing sequence-nonspecific stabilization of peptide dimers in lipid raft-like bilayers
摘要：Increased levels of cholesterol and saturated fatty acids (FAs) in immune cell membranes have proinflammatory effects. As opposed to specific effects of lipids mediated by certain lipid-protein interactions, non-specific and indirect effects of such lipids that regulate protein dynamics, regardless of their sequence, could have played influential roles in the early stages of evolution of life. Our recent atomistic simulations showed that, compared to bilayers with abundant unsaturated acyl chains, raft-like bilayers rich in cholesterol and saturated FA chains exert an effect to stabilize the dimeric state of transmembrane helical peptides with simple sequences. The energy cost associated with desolvation of the peptides from lipids upon dimerization was less in the raft-like bilayers compared to unsaturated FA-rich bilayers, suggesting that solvation (or fitting) of peptides by lipids is important for the dimer-stabilizing effects of such bilayers. In our simulations, acyl chains of phospholipids, but not cholesterol, directly solvated peptides. It is hypothesized that the peptide dimer-stabilizing effect may be the origin of the pro-inflammatory effects of cholesterol and saturated FAs. In this commentary, we mainly discuss our observations in atomistic simulations with some considerations on related experiments and computations as well as on recent knowledge on the properties of various membrane microdomains.
