Chain-length-dependent partitioning of 1-alkanols in raft-like lipid membranes

Abstract

Although 1-alkanols are widely used as anesthetics and membrane-active agents, the molecular basis of their chain-length-dependent cutoff behavior remains unclear. Here, we perform extensive atomistic molecular dynamics simulations to investigate the partitioning of 1-alkanols with varying chain lengths in a raft-like lipid bilayer composed of dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylcholine (DOPC), and cholesterol (Chol), which exhibits coexistence of liquid-ordered (lo) and liquid-disordered (ld) domains. We observe pronounced lateral heterogeneity in alkanol distribution, membrane thickness, number density, and lateral pressure profiles across coexisting phases. A distinct cutoff chain length, ncutoff = 12, is identified: alkanols with n < ncutoff preferentially partition into DOPC-rich ld domains, whereas alkanols with n ≥ ncutoff preferentially localize within DPPC- and cholesterol-rich lo domains. Our results indicate a reduction in the magnitude of the lateral pressure profile and the associated elastic moments upon incorporation of 1-alkanols relative to the alkanol-free membrane, within statistical uncertainty. The results provide a detailed molecular characterization of how alkanol chain length modulates the membrane structure and mechanical response in laterally heterogeneous lipid membranes.