Centi Alessia, Dutta Arghya, Parekh Sapun H, Bereau Tristan
Max Planck Institute for Polymer Research, Mainz, Germany.
Max Planck Institute for Polymer Research, Mainz, Germany; Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas.
Biophys J. 2020 Mar 24;118(6):1321-1332. doi: 10.1016/j.bpj.2020.01.039. Epub 2020 Feb 4.
Small solutes have been shown to alter the lateral organization of cell membranes and reconstituted phospholipid bilayers; however, the mechanisms by which these changes happen are still largely unknown. Traditionally, both experiment and simulation studies have been restricted to testing only a few compounds at a time, failing to identify general molecular descriptors or chemical properties that would allow extrapolating beyond the subset of considered solutes. In this work, we probe the competing energetics of inserting a solute in different membrane environments by means of the potential of mean force. We show that these calculations can be used as a computationally efficient proxy to establish whether a solute will stabilize or destabilize domain phase separation. Combined with umbrella-sampling simulations and coarse-grained molecular dynamics simulations, we are able to screen solutes across a wide range of chemistries and polarities. Our results indicate that for the system under consideration, preferential partitioning and therefore effectiveness in altering membrane phase separation are strictly linked to the location of insertion in the bilayer (i.e., midplane or interface). Our approach represents a fast and simple tool for obtaining structural and thermodynamic insight into the partitioning of small molecules between lipid domains and its relation to phase separation, ultimately providing a platform for identifying the key determinants of this process.
已表明小分子溶质会改变细胞膜和重构磷脂双层的侧向组织；然而，这些变化发生的机制在很大程度上仍不清楚。传统上，实验和模拟研究都局限于一次仅测试几种化合物，未能识别出能够外推到所考虑溶质子集之外的通用分子描述符或化学性质。在这项工作中，我们借助平均力势来探究在不同膜环境中插入溶质的竞争能量学。我们表明，这些计算可以用作一种计算效率高的代理，以确定溶质是否会稳定或破坏域相分离。结合伞形采样模拟和粗粒化分子动力学模拟，我们能够筛选各种化学性质和极性的溶质。我们的结果表明，对于所考虑的系统，优先分配以及因此改变膜相分离的有效性与在双层中的插入位置（即中平面或界面）密切相关。我们的方法代表了一种快速且简单的工具，用于获得关于小分子在脂质域之间分配的结构和热力学见解及其与相分离的关系，最终提供一个识别该过程关键决定因素的平台。
