Bubnis Greg, Grubmüller Helmut
Department of Theoretical and Computational Biophysics, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany; Weill Institute for Neurosciences and Department of Neurology, University of California San Francisco, San Francisco, California.
Department of Theoretical and Computational Biophysics, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany.
Biophys J. 2020 Dec 15;119(12):2418-2430. doi: 10.1016/j.bpj.2020.10.037. Epub 2020 Nov 13.
Membrane topology changes such as poration, stalk formation, and hemifusion rupture are essential to cellular function, but their molecular details, energetics, and kinetics are still not fully understood. Here, we present a unified energetic and mechanistic picture of metastable pore defects in tensionless lipid membranes. We used an exhaustive committor analysis to test and select optimal reaction coordinates and also to determine the nucleation mechanism. These reaction coordinates were used to calculate free-energy landscapes that capture the full process and end states. The identified barriers agree with the committor analysis. To enable sufficient sampling of the complete transition path for our molecular dynamics simulations, we developed a "gizmo" potential biasing scheme. The simulations suggest that the essential step in the nucleation is the initial merger of lipid headgroups at the nascent pore center. To facilitate this event, an indentation pathway is energetically preferred to a hydrophobic defect. Continuous water columns that span the indentation were determined to be on-path transients that precede the nucleation barrier. This study gives a quantitative description of the nucleation mechanism and energetics of small metastable pores and illustrates a systematic approach to uncover the mechanisms of diverse cellular membrane remodeling processes.
膜拓扑结构的变化，如形成孔道、茎状结构和半融合破裂，对细胞功能至关重要，但其分子细节、能量学和动力学仍未完全了解。在此，我们展示了无张力脂质膜中亚稳态孔缺陷的统一能量学和力学图景。我们使用了详尽的终态分析来测试和选择最佳反应坐标，并确定成核机制。这些反应坐标用于计算能够捕捉整个过程和终态的自由能景观。所确定的势垒与终态分析结果一致。为了在我们的分子动力学模拟中对完整的过渡路径进行充分采样，我们开发了一种“小装置”势偏置方案。模拟结果表明，成核过程中的关键步骤是新生孔中心处脂质头部基团的初始合并。为促成这一事件，与疏水缺陷相比，压痕路径在能量上更具优势。跨越压痕的连续水柱被确定为成核势垒之前的路径上的瞬态。这项研究对小亚稳态孔的成核机制和能量学进行了定量描述，并阐明了一种揭示各种细胞膜重塑过程机制的系统方法。
