使用配体竞争饱和位点识别的脂质双层中的官能团分布、分配系数和阻力因子,Journal of Chemical Theory and Computation

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使用配体竞争饱和位点识别的脂质双层中的官能团分布、分配系数和阻力因子
Journal of Chemical Theory and Computation ( IF 5.7 ) Pub Date : 2021-04-30 , DOI: 10.1021/acs.jctc.1c00089
Christoffer Lind ₁ , Poonam Pandey ₁ , Richard W Pastor ₂ , Alexander D MacKerell ₁

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代谢物和药物等小分子必须通过细胞膜，这是一种主要由磷脂双层和嵌入蛋白质组成的屏障。为了更好地理解被动扩散过程，了解各种官能团跨双层分配的能力和相关的能量学将是有用的。在本研究中，通过配体竞争饱和 (SILCS) 方法进行的位点识别已被应用于对代表小分子官能团的各种化学溶质的分布进行采样，这些溶质代表跨由 0.9:0.1 1-palmitoyl-2 组成的磷脂双层-oleoyl- sn -glycero -3-phosphocholine/cholesterol 和 0.52:0.18:0.3 1,2- dioleoyl- sn -glycero-3-phospho - l的混合物-丝氨酸/1,2-二油酰-sn-glycero-3-phosphocholine/cholesterol 用于平行人工膜渗透性测定实验。在 SILCS 模拟中应用了振荡化学势大规范蒙特卡罗和分子动力学的组合，以通过双层和周围的水环境实现溶质取样，从中获得溶质的分布和它们所代表的官能团。结果显示脂肪族与芳香族基团的分布不同，前者在双层中心的取样增加，而后者在甘油接头区域的取样增加。不同极性基团的分布差异明显，负乙酸盐和正甲基铵之间的差异很大，极性中性和乙酸盐溶质在双层头部基团上方积累。将分布转换为绝对自由能可以详细了解双层不同区域中官能团的能量学，并可以计算跨双层的多功能药物样分子的绝对自由能分布，其中分配系数和阻力因子适合插入均质溶解度-扩散方程以计算渗透率。将计算出的双层/溶液分配系数与 1-辛醇/水的类药物分子和溶质的实验数据进行比较，显示出总体上良好的一致性，

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Functional Group Distributions, Partition Coefficients, and Resistance Factors in Lipid Bilayers Using Site Identification by Ligand Competitive Saturation

Small molecules such as metabolites and drugs must pass through the membrane of the cell, a barrier primarily comprising phospholipid bilayers and embedded proteins. To better understand the process of passive diffusion, knowledge of the ability of various functional groups to partition across bilayers and the associated energetics would be of utility. In the present study, the site identification by ligand competitive saturation (SILCS) methodology has been applied to sample the distributions of a diverse set of chemical solutes representing the functional groups of small molecules across phospholipid bilayers composed of 0.9:0.1 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine/cholesterol and a mixture of 0.52:0.18:0.3 1,2-dioleoyl-sn-glycero-3-phospho-l-serine/1,2-dioleoyl-sn-glycero-3-phosphocholine/cholesterol used in parallel artificial membrane permeability assay experiments. A combination of oscillating chemical potential grand canonical Monte Carlo and molecular dynamics in the SILCS simulations was applied to achieve solute sampling through the bilayers and surrounding aqueous environment from which the distribution of solutes and the functional groups they represent were obtained. Results show differential distribution of aliphatic versus aromatic groups with the former having increased sampling in the center of the bilayers versus in the region of the glycerol linker for the latter. Variations in the distribution of different polar groups are evident, with large differences between negative acetate and positive methylammonium with accumulation of the polar-neutral and acetate solutes above the bilayer head groups. Conversion of the distributions to absolute free energies allows for a detailed understanding of energetics of functional groups in different regions of the bilayers and for calculation of absolute free-energy profiles of multifunctional drug-like molecules across the bilayers from which partition coefficients and resistance factors suitable for insertion into the homogenous solubility–diffusion equation for calculation of permeability were obtained. Comparisons of the calculated bilayer/solution partition coefficients with 1-octanol/water experimental data for both drug-like molecules and the solutes show overall good agreement, validating the calculated distributions and associated absolute free-energy profiles.

更新日期：2021-05-11

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