Rivel Timothée, Biriukov Denys, Kabelka Ivo, Vácha Robert
Central European Institute of Technology, Masaryk University, Kamenice 5, CZ-62500 Brno, Czech Republic.
National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kamenice 5, CZ-62500 Brno, Czech Republic.
J Chem Inf Model. 2025 Jan 27;65(2):908-920. doi: 10.1021/acs.jcim.4c01960. Epub 2025 Jan 10.
Understanding the molecular mechanisms of pore formation is crucial for elucidating fundamental biological processes and developing therapeutic strategies, such as the design of drug delivery systems and antimicrobial agents. Although experimental methods can provide valuable information, they often lack the temporal and spatial resolution necessary to fully capture the dynamic stages of pore formation. In this study, we present two novel collective variables (CVs) designed to characterize membrane pore behavior, particularly its energetics, through molecular dynamics (MD) simulations. The first CV─termed Full-Path─effectively tracks both the nucleation and expansion phases of pore formation. The second CV─called Rapid─is tailored to accurately assess pore expansion in the limit of large pores, providing quick and reliable method for evaluating membrane line tension under various conditions. Our results clearly demonstrate that the line tension predictions from both our CVs are in excellent agreement. Moreover, these predictions align qualitatively with available experimental data. Specifically, they reflect higher line tension of 1-palmitoyl-2-oleoyl--glycero-3-phosphocholine (POPC) membranes containing 1-palmitoyl-2-oleoyl--glycero-3-phospho-l-serine (POPS) lipids compared to pure POPC, the decrease in line tension of POPC vesicles as the 1-palmitoyl-2-oleoyl--glycero-3-phosphoglycerol (POPG) content increases, and higher line tension when ionic concentration is increased. Notably, these experimental trends are accurately captured only by the all-atom CHARMM36 and prosECCo75 force fields. In contrast, the all-atom Slipids force field, along with the coarse-grained Martini 2.2, Martini 2.2 polarizable, and Martini 3 models, show varying degrees of agreement with experiments. Our developed CVs can be adapted to various MD simulation engines for studying pore formation, with potential implications in membrane biophysics. They are also applicable to simulations involving external agents, offering an efficient alternative to existing methodologies.
理解孔形成的分子机制对于阐明基本生物学过程和开发治疗策略至关重要，例如药物递送系统和抗菌剂的设计。尽管实验方法可以提供有价值的信息，但它们往往缺乏全面捕捉孔形成动态阶段所需的时间和空间分辨率。在本研究中，我们提出了两个新的集体变量（CVs），旨在通过分子动力学（MD）模拟来表征膜孔行为，特别是其能量学。第一个CV——称为全路径（Full-Path）——有效地跟踪孔形成的成核和扩展阶段。第二个CV——称为快速（Rapid）——专为在大孔极限下准确评估孔扩展而设计，为评估各种条件下的膜线张力提供了快速可靠的方法。我们的结果清楚地表明，来自两个CVs的线张力预测结果非常一致。此外，这些预测在定性上与现有实验数据相符。具体而言，它们反映出与纯1-棕榈酰-2-油酰基-sn-甘油-3-磷酸胆碱（POPC）相比，含有1-棕榈酰-2-油酰基-sn-甘油-3-磷酸-L-丝氨酸（POPS）脂质的POPC膜具有更高的线张力；随着1-棕榈酰-2-油酰基-sn-甘油-3-磷酸甘油（POPG）含量的增加，POPC囊泡的线张力降低；以及离子浓度增加时线张力更高。值得注意的是，只有全原子CHARMM36和prosECCo75力场才能准确捕捉这些实验趋势。相比之下，全原子Slipids力场以及粗粒化的Martini 2.2、Martini 2.2可极化和Martini 3模型与实验结果的吻合程度各不相同。我们开发的CVs可适用于各种MD模拟引擎来研究孔形成，对膜生物物理学具有潜在影响。它们也适用于涉及外部试剂的模拟，为现有方法提供了一种有效的替代方案。
