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, we present a new RC capable of driving both pore nucleation and pore expansion in lipid membranes. The potential of mean force (PMF) along the RC computed with molecular dynamics (MD) 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. We illustrate the RC by quantifying the effects (i) of simulation system size and (ii) of the addition of dimethyl sulfoxide (DMSO) 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.

中文翻译：

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用于计算脂质膜中孔核化和孔扩展的自由能态的联合反应坐标

膜的拓扑转变，例如孔形成或膜融合，在生物学，生物技术和医学应用中起着关键作用。由于相关过程涉及构象空间中沿高度不同方向的一系列跃迁，因此计算相关的自由能态势非常复杂，因此很难为整个过程定义良好的反应坐标（RC）。在这项研究中，我们提出了一种新型的RC，它能够驱动脂质膜中的孔核化和孔扩展。通过分子动力学（MD）模拟计算得出的沿RC的平均力（PMF）势能全面了解孔形成的自由能态势，包括孔成核的障碍，尺寸，自由能和亚稳开孔 以及针对孔边缘的线张力进一步扩大孔的能量成本。我们通过量化（i）模拟系统尺寸和（ii）添加二甲基亚砜（DMSO）对孔形成的自由能态的影响来说明RC。沿RC进行的PMF计算提供了对孔形成的机理和能量的理解，因此对于合理化膜活性肽，电场和膜成分对跨膜孔的影响将很有用。