The collective behavior of lipids with diverse chemical and physical features determines a membrane’s thermodynamic properties. Yet, the influence of lipid physicochemical properties on lipid dynamics, in particular interbilayer transport, remains underexplored. Here, we systematically investigate how the activation free energy of passive lipid transport depends on lipid chemistry and membrane phase. Through all-atom molecular dynamics simulations of 11 chemically distinct glycerophospholipids, we determine how lipid acyl chain length, unsaturation, and headgroup influence the free energy barriers for two elementary steps of lipid transport: lipid desorption, which is rate limiting, and lipid insertion into a membrane. Consistent with previous experimental measurements, we find that lipids with longer, saturated acyl chains have increased activation free energies compared to lipids with shorter, unsaturated chains. Lipids with different headgroups exhibit a range of activation free energies; however, no clear trend based solely on chemical structure can be identified, mirroring difficulties in the interpretation of previous experimental results. Compared to liquid-crystalline phase membranes, gel phase membranes exhibit substantially increased free energy barriers. Overall, we find that the activation free energy depends on a lipid’s local hydrophobic environment in a membrane and that the free energy barrier for lipid insertion depends on a membrane’s interfacial hydrophobicity. Both of these properties can be altered through changes in lipid acyl chain length, lipid headgroup, and membrane phase. Thus, the rate of lipid transport can be tuned through subtle changes in local membrane composition and order, suggesting an unappreciated role for nanoscale membrane domains in regulating cellular lipid dynamics.

具有不同化学和物理特征的脂质的集体行为决定了膜的热力学特性。然而，脂质物理化学性质对脂质动力学的影响，特别是双层间运输，仍未得到充分探索。在这里，我们系统地研究了被动脂质转运的活化自由能如何依赖于脂质化学和膜相。通过对 11 种化学性质不同的甘油磷脂进行全原子分子动力学模拟，我们确定了脂质酰基链长度、不饱和度和头部基团如何影响脂质转运的两个基本步骤的自由能垒：脂质解吸（速率限制）和脂质插入膜。与之前的实验测量结果一致，我们发现脂质较长，与具有较短不饱和链的脂质相比，饱和酰基链具有增加的活化自由能。具有不同头部基团的脂质表现出一系列活化自由能；然而，无法确定仅基于化学结构的明确趋势，这反映了对先前实验结果的解释困难。与液晶相膜相比，凝胶相膜表现出显着增加的自由能势垒。总的来说，我们发现活化自由能取决于膜中脂质的局部疏水环境，而脂质插入的自由能屏障取决于膜的界面疏水性。这两种性质都可以通过脂质酰基链长度、脂质头基和膜相的变化来改变。因此，