Lev Bogdan, Vorobyov Igor, Clarke Ronald J, Allen Toby W
School of Science, RMIT University, GPO Box 2476, Melbourne, VIC 3001, Australia.
Department of Physiology and Membrane Biology/Department of Pharmacology, University of California, Davis, 4303 Tupper Hall, One Shields Avenue, Davis, California 95616, United States.
J Phys Chem B. 2024 Oct 3;128(39):9482-9499. doi: 10.1021/acs.jpcb.4c04469. Epub 2024 Sep 20.
Understanding membrane charge transport processes, including the actions of ion channels, pumps, carriers, and membrane-active peptides, requires a description of the electrostatics of the lipid bilayer. We have simulated a library of different lipid chemistries to reveal the impact of the headgroup, glycerol backbone, and hydrocarbon chains on the membrane dipole potential. We found a strong dependence of the potential on lipid packing, but this was not caused by the packing of lipid polar components, due to cancellation of their electric fields by electrolyte. In contrast, lipid tail contributions were determined by area per lipid, arising from two countering effects. Increased area per lipid leads to chain tilting that increases methylene dipole projections to strengthen the electric field within the bilayer, while at the same time decreasing the electric field from terminal methyl groups. Moreover, electric fields from some nonterminal groups and the terminal methyl group can extend beyond the bilayer center and be canceled by the opposing leaflet. This interleaflet field annulment explains the experimental reduction in dipole potential for unsaturated and branched lipid bilayers, by as much as ∼200 mV, as well as experiments that substitute chain carbons with sulfur. Replacing ester with ether groups (eliminating two carbonyl groups) causes a significant reduction in potential, also by ∼200 mV, in agreement with experiment. We show that the effect can be largely attributed to the loss of aligned water molecules in the glycerol backbone region, lowering the potential inside the bilayer core. When only one of the two carbonyls is removed (using a hybrid ester-ether lipid or a single-chain lipid), most of this reduction in potential was lost, with the single carbonyl group able to maintain full hydration in the interfacial region. While headgroup chemistry can have a major effect (by as much as ±100 mV relative to phosphatidylcholine), anionic headgroups either decrease or increase the dipole potential, with the variation involving perturbation in hydrogen-bonded water molecules and changes in packing of lipid tails. Overall, these results suggest that membrane electrostatics are dominated by aligned water molecules at the polar-hydrocarbon interface and, surprisingly, by the charge distribution of the nonpolar lipid tails, and not the packing of headgroup and glycerol carbonyl dipoles.
理解膜电荷传输过程，包括离子通道、泵、载体和膜活性肽的作用，需要对脂质双层的静电学进行描述。我们模拟了一系列不同的脂质化学结构，以揭示头基团、甘油主链和烃链对膜偶极子电位的影响。我们发现电位强烈依赖于脂质堆积，但这并非由脂质极性成分的堆积引起，因为电解质会抵消它们的电场。相反，脂质尾部的贡献由每个脂质的面积决定，这源于两种相反的效应。每个脂质面积的增加会导致链倾斜，从而增加亚甲基偶极子投影，增强双层内的电场，同时降低末端甲基的电场。此外，一些非末端基团和末端甲基的电场可以延伸到双层中心之外，并被相对的小叶抵消。这种小叶间电场抵消解释了不饱和和支链脂质双层偶极子电位实验中高达约200 mV的降低，以及用硫替代链碳的实验结果。用醚基取代酯基（消除两个羰基）会导致电位显著降低，同样约为200 mV，这与实验结果一致。我们表明，这种效应在很大程度上可归因于甘油主链区域排列的水分子的损失，降低了双层核心内部的电位。当仅去除两个羰基中的一个（使用混合酯 - 醚脂质或单链脂质）时，大部分电位降低消失，单个羰基能够在界面区域保持完全水合。虽然头基团化学可以产生重大影响（相对于磷脂酰胆碱高达±100 mV），但阴离子头基团要么降低要么增加偶极子电位，这种变化涉及氢键结合水分子的扰动和脂质尾部堆积的变化。总体而言，这些结果表明膜静电学主要由极性 - 烃界面处排列的水分子以及令人惊讶的非极性脂质尾部的电荷分布主导，而不是头基团和甘油羰基偶极子的堆积。
