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 ($l_o$) and liquid-disordered ($l_d$) 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, $n_{cutoff}=12$, is identified: alkanols with $n<n_{cutoff}$ preferentially partition into DOPC-rich $l_d$ domains, whereas alkanols with $n \ge n_{cutoff}$ preferentially localize within DPPC- and cholesterol-rich $l_o$ domains. This chain-length-dependent redistribution is accompanied by systematic reductions in the lateral pressure profile, membrane compressibility, and bending rigidity of the bilayer. The results provide a detailed molecular characterization of how alkanol chain length modulates membrane structure and mechanical response in laterally heterogeneous lipid membranes.