Theoretical Physics and Center for Biophysics, Saarland University, Saarbrücken D-66123, Germany.
J Chem Theory Comput. 2021 Feb 9;17(2):1229-1239. doi: 10.1021/acs.jctc.0c01134. Epub 2021 Jan 11.
Topological transitions of membranes, such as pore formation or membrane fusion, play key roles in biology, biotechnology, and in medical applications. Calculating the related free-energy landscapes has been complicated by the fact that such processes involve a sequence of transitions along highly distinct directions in conformational space, making it difficult to define good reaction coordinates (RCs) for the overall process. In this study, a new RC capable of driving both pore nucleation and pore expansion in lipid membranes is presented. The potential of mean force (PMF) along the RC computed with molecular dynamics simulations provides a comprehensive view on the free-energy landscape of pore formation, including a barrier for pore nucleation; the size, free energy, and metastability of the open pore; and the energetic cost for further pore expansion against the line tension of the pore rim. The RC is illustrated by quantifying the effects of (i) simulation system size and (ii) the addition of dimethyl sulfoxide on the free-energy landscape of pore formation. PMF calculations along the RC provide mechanistic and energetic understanding of pore formation, hence they will be useful to rationalize the effects of membrane-active peptides, electric fields, and membrane composition on transmembrane pores.
膜的拓扑转变，如孔形成或膜融合，在生物学、生物技术和医学应用中起着关键作用。由于这些过程涉及沿构象空间中高度不同的方向进行一系列转变，因此计算相关的自由能景观变得复杂，难以定义整个过程的良好反应坐标 (RC)。在这项研究中，提出了一种能够驱动脂质膜中孔核形成和孔扩展的新 RC。使用分子动力学模拟计算沿 RC 的平均力势 (PMF) 提供了孔形成自由能景观的全面视图，包括孔核形成的势垒；开口孔的大小、自由能和亚稳定性；以及与孔边缘的线张力相对抗的进一步孔扩展的能量成本。通过量化 (i) 模拟系统大小和 (ii) 添加二甲亚砜对孔形成自由能景观的影响，说明了 RC。沿 RC 的 PMF 计算提供了对孔形成的机制和能量理解，因此它们将有助于合理说明膜活性肽、电场和膜组成对跨膜孔的影响。
