Institute for Theoretical Physics, University of Goettingen, Friedrich-Hund-Platz 1, 37077 Göttingen, Germany.
J Chem Phys. 2017 Aug 14;147(6):064906. doi: 10.1063/1.4997575.
Membrane fission is a fundamental process in cells, involved inter alia in endocytosis, intracellular trafficking, and virus infection. Its underlying molecular mechanism, however, is only incompletely understood. Recently, experiments and computer simulation studies have revealed that dynamin-mediated membrane fission is a two-step process that proceeds via a metastable hemi-fission intermediate (or wormlike micelle) formed by dynamin's constriction. Importantly, this hemi-fission intermediate is remarkably metastable, i.e., its subsequent rupture that completes the fission process does not occur spontaneously but requires additional, external effects, e.g., dynamin's (unknown) conformational changes or membrane tension. Using simulations of a coarse-grained, implicit-solvent model of lipid membranes, we investigate the molecular mechanism of rupturing the hemi-fission intermediate, such as its pathway, the concomitant transition states, and barriers, as well as the role of membrane tension. The membrane tension is controlled by the chemical potential of the lipids, and the free-energy landscape as a function of two reaction coordinates is obtained by grand canonical Wang-Landau sampling. Our results show that, in the course of rupturing, the hemi-fission intermediate undergoes a "thinning → local pinching → rupture/fission" pathway, with a bottle-neck-shaped cylindrical micelle as a transition state. Although an increase of membrane tension facilitates the fission process by reducing the corresponding free-energy barrier, for biologically relevant tensions, the free-energy barriers still significantly exceed the thermal energy scale kT.
膜裂变是细胞中的一个基本过程，涉及内吞作用、细胞内运输和病毒感染等过程。然而，其潜在的分子机制尚不完全清楚。最近的实验和计算机模拟研究表明，dynamin 介导的膜裂变是一个两步过程，通过 dynamin 的收缩形成一个亚稳定的半裂变中间体（或蠕虫状胶束）进行。重要的是，这个半裂变中间体非常稳定，即随后完成裂变过程的破裂不会自发发生，而是需要额外的外部效应，例如 dynamin 的（未知）构象变化或膜张力。我们使用脂质膜的粗粒度隐溶剂模型的模拟来研究打破半裂变中间体的分子机制，例如其途径、伴随的过渡态和势垒，以及膜张力的作用。膜张力由脂质的化学势控制，通过巨正则 Wang-Landau 抽样获得两个反应坐标的自由能景观。我们的结果表明，在破裂过程中，半裂变中间体经历了“变薄→局部挤压→破裂/裂变”途径，具有瓶颈状的圆柱形胶束作为过渡态。尽管增加膜张力通过降低相应的自由能势垒有助于裂变过程，但对于生物学上相关的张力，自由能势垒仍然显著超过热能量标 kT。
