Permeability of a Fluid Lipid Bilayer to Short-Chain Alcohols from First Principles
Permeability of a Fluid Lipid Bilayer to Short-Chain Alcohols from First Principles
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DOI：
10.1021/acs.jctc.7b00264
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发表时间：
2017-06-01
影响因子：
5.5
通讯作者：
Chipot, Christophe
中科院分区：
文献类型：
--
作者：
Comer, Jeffrey;Schulten, Klaus;Chipot, Christophe
计算预测的膜渗透性的小分子需要准确描述的热力学和动力学的跨脂质双层的移位。在这方面的贡献，以及收敛，微秒长的自由能计算相结合，最近开发的subdiffusive动力学框架来描述膜渗透的同源系列的短尾醇，从甲醇到1-biltanol，前所未有的保真度的基础分子模型。虽然自由能的档案表现出沐浴者通过中心的双层在所有情况下，这些障碍的高度随着脂肪链的长度的醇，在定量协议与实验确定的微分溶剂化自由能在水和油。本文采用的subdiffusive模型的一个独特的方面，这是在以前的文章中开发的，是一个位置依赖的分数阶的确定，其量化的程度，醇的运动偏离经典扩散沿着膜的厚度。在远离双层的水性介质中，这个量接近1.0，纯经典扩散的渐近极限，而它在膜中心附近低于0.75，与渗透物无关。值得注意的是，附近的膜的中心，它的渗透性的影响是最大的分数扩散系数，是相似的，尽管甲醇和1-丁醇之间的分子量和亲油性的大的差异，在四个渗透。因此，根据自由能和分数扩散率分布估计的相对渗透率主要由前者而不是后者的差异决定。预测的相对渗透率与现有的实验结果是高度相关的，虽然他们不同意定量与他们。另一方面，非常出乎意料的是，短尾醇的报告实验值比水的可用实验测量值低近三个数量级。这种明显的理论和实验之间的分歧的合理解释被认为是详细的。
Computational prediction of membrane permeability to small molecules requires accurate description of both the thermodynamics and kinetics underlying trans location across the lipid bilayer. In this contribution, well converged, microsecond-long free-energy calculations are combined with a recently developed subdiffusive kinetics framework to describe the membrane permeation of a homologous series of short-tail alcohols, from methanol to 1-biltanol, with unprecedented fidelity to the underlying molecular models. While the free-energy profiles exhibit bathers for passage through the center of the bilayer in all cases, the height of these barriers decreases with the length of the aliphatic chain of the alcohol, in quantitative agreement with experimentally determined differential solvation free energies in water and oil. A unique aspect of the subdiffusive model employed herein, which was developed in a previous article, is the determination of a position-dependent fractional order which quantifies the degree to which the motion of the alcohol deviates from classical diffusion along the thickness of the membrane. In the aqueous medium far from the bilayer, this quantity approaches 1.0, the asymptotic limit for purely classical diffusion, whereas it dips below 0.75 near the center of the membrane irrespective of the permeant. Remarkably, the fractional diffusivity near the center of membrane, where its influence on the permeability is the greatest, is similar among the four permeants despite the large difference in molecular weight and lipophilicity between methanol and 1-butanol. The relative permeabilities, which are estimated from the free-energy and fractional diffusivity profiles, are therefore determined predominantly by differences in the former rather than the latter. The predicted relative permeabilities are highly correlated with existing experimental results, albeit they do not agree quantitatively with them. On the other hand, quite unexpectedly, the reported experimental values for the short-tail alcohols are nearly three orders of magnitude lower than the available experimental measurement for water. Plausible explanations for this apparent disagreement between theory and experiment are considered in detail.