Graduate Program in Biophysics, University of Wisconsin, Madison, Wisconsin, USA.
Biophys J. 2013 Jan 8;104(1):128-38. doi: 10.1016/j.bpj.2012.11.3813.
To further foster the connection between particle based and continuum mechanics models for membrane mediated biological processes, we carried out coarse-grained (CG) simulations of gramicidin A (gA) dimer association and analyzed the results based on the combination of potential of mean force (PMF) and stress field calculations. Similar to previous studies, we observe that the association of gA dimers depends critically on the degree of hydrophobic mismatch, with the estimated binding free energy of >10 kcal/mol in a distearoylphosphatidylcholine bilayer. Qualitative trends in the computed PMF can be understood based on the stress field distributions near a single gA dimer and between a pair of gA dimers. For example, the small PMF barrier, which is ∼1 kcal/mol independent of lipid type, can be captured nearly quantitatively by considering membrane deformation energy associated with the region confined by two gA dimers. However, the PMF well depth is reproduced poorly by a simple continuum model that only considers membrane deformation energy beyond the annular lipids. Analysis of lipid orientation, configuration entropy, and stress distribution suggests that the annular lipids make a significant contribution to the association of two gA dimers. These results highlight the importance of explicitly considering contributions from annular lipids when constructing approximate models to study processes that involve a significant reorganization of lipids near proteins, such as protein-protein association and protein insertion into biomembranes. Finally, large-scale CG simulations indicate that multiple gA dimers also form clusters, although the preferred topology depends on the protein concentration. Even at high protein concentrations, every gA dimer requires contact to lipid hydrocarbons to some degree, and at most three to four proteins are in contact with each gA dimer; this observation highlights another aspect of the importance of interactions between proteins and annular lipids.
为了进一步促进基于粒子和连续介质力学模型在膜介导生物过程中的联系，我们对革兰氏菌素 A（gA）二聚体的聚集进行了粗粒化（CG）模拟，并基于平均力势（PMF）和应力场计算的组合分析了结果。与以前的研究类似，我们观察到 gA 二聚体的聚集严重依赖于疏水性失配的程度，在二硬脂酰磷脂酰胆碱双层中，估计的结合自由能>10 kcal/mol。基于单个 gA 二聚体附近和两个 gA 二聚体之间的应力场分布，可以理解计算出的 PMF 的定性趋势。例如，与脂质类型无关的约 1 kcal/mol 的小 PMF 势垒，可以通过考虑与两个 gA 二聚体限制的区域相关的膜变形能几乎定量地捕获。然而，简单的连续介质模型对 PMF 势阱深度的再现效果很差，该模型仅考虑了环形脂质之外的膜变形能。脂质取向、构象熵和应力分布的分析表明，环形脂质对两个 gA 二聚体的聚集有重要贡献。这些结果强调了在构建近似模型以研究涉及蛋白质附近脂质显著重排的过程（如蛋白质-蛋白质相互作用和蛋白质插入生物膜）时，明确考虑环形脂质贡献的重要性。最后，大规模 CG 模拟表明，多个 gA 二聚体也形成簇，尽管首选拓扑结构取决于蛋白质浓度。即使在高蛋白质浓度下，每个 gA 二聚体在某种程度上都需要与脂质烃接触，并且最多有三到四个蛋白质与每个 gA 二聚体接触；这一观察结果突出了蛋白质与环形脂质之间相互作用的重要性的另一个方面。
