Theoretical Physics and Center for Biophysics, Saarland University, 66123 Saarbrücken, Germany.
Phys Rev Lett. 2024 Apr 5;132(14):148401. doi: 10.1103/PhysRevLett.132.148401.
The formation of pores over lipid membranes by the application of electric fields, termed membrane electroporation, is widely used in biotechnology and medicine to deliver drugs, vaccines, or genes into living cells. Continuum models for describing the free energy landscape of membrane electroporation were proposed decades ago, but they have never been tested against spatially detailed atomistic models. Using molecular dynamics (MD) simulations with a recently proposed reaction coordinate, we computed potentials of mean force of pore nucleation and pore expansion in lipid membranes at various transmembrane potentials. Whereas the free energies of pore expansion are compatible with previous continuum models, the experimentally important free energy barrier of pore nucleation is at variance with established models. The discrepancy originates from different geometries of the transition state; previous continuum models assumed the presence of a membrane-spanning defect throughout the process, whereas, according to the MD simulations, the transition state of pore nucleation is typically passed before a transmembrane defect has formed. A modified continuum model is presented that qualitatively agrees with the MD simulations. Using kinetics of pore opening together with transition state theory, our free energies of pore nucleation are in excellent agreement with previous experimental data.
通过施加电场在脂质膜上形成孔，称为膜电穿孔，广泛用于生物技术和医学领域，将药物、疫苗或基因递送到活细胞中。几十年来，人们提出了用于描述膜电穿孔自由能景观的连续体模型，但这些模型从未与空间详细的原子模型进行过对比测试。我们使用最近提出的反应坐标的分子动力学 (MD) 模拟，在各种跨膜电势下计算了脂质膜中孔核和孔扩展的平均力势。虽然孔扩展的自由能与以前的连续体模型兼容，但实验上重要的孔核自由能势垒与已建立的模型不一致。这种差异源于过渡态的不同几何形状；以前的连续体模型假设在整个过程中存在一个跨膜缺陷，而根据 MD 模拟，孔核的过渡态通常是在形成跨膜缺陷之前通过的。提出了一个修正的连续体模型，它与 MD 模拟定性上一致。通过使用孔打开的动力学和过渡态理论，我们的孔核自由能与以前的实验数据非常吻合。
