Abstract：
We conducted a series of coarse-grained molecular dynamics (CG-MD) simulations to investigate the complicated actions of melittin, which is an antimicrobial peptide (AMP) derived from honey bee venom, on a lipid membrane. To accurately simulate the AMP action, we developed and used a protein CG model as an extension of the pSPICA force field (FF), which was designed to reproduce several thermodynamic quantities and structural properties. At a low peptide-to-lipid (P/L) ratio (1/102), no defect was detected. At P/L = 1/51, toroidal pore formation was observed due to collective insertion of multiple melittin peptides from the N-termini. The pore formation was initiated by a local increase in membrane curvature in the vicinity of the peptide aggregate. At a higher P/L ratio (1/26), two more modes were detected, seemingly not controlled by the P/L ratio but by a local arrangement of melittin peptides: 1. Pore formation accompanied by lipid extraction by melittin peptides:a detergent-like mechanism. 2. A rapidly formed large pore in a significantly curved membrane: bursting. Thus, we observed three pore formation modes (toroidal pore formation, lipid extraction, and bursting) depending on the peptide concentration and local arrangement. These observations were consistent with experimental observations and hypothesized melittin modes. Through this study, we found that the local arrangements and population of melittin peptides and the area expansion rate by membrane deformation were key to the initiation of and competition among the multiple pore formation mechanisms.
摘要：
我们进行了一系列粗粒分子动力学（CG-MD）模拟，以研究蜂毒素的复杂作用，它是一种来源于蜜蜂毒液的抗菌肽(AMP),在脂质膜上。为了准确模拟AMP动作，我们开发并使用蛋白质CG模型作为pSPICA力场（FF）的扩展，它被设计用来再现几个热力学量和结构性质。在低肽与脂质（P/L）比率（1/102）下，没有检测到缺陷。在P/L=1/51时，由于多个蜂毒素肽从N末端的集体插入，观察到了环形孔的形成。通过在肽聚集体附近的膜曲率的局部增加来引发孔形成。在较高的市盈率(1/26)下，检测到另外两种模式，似乎不受P/L比率的控制，而是受蜂毒素肽的局部排列控制：1。蜂毒素肽伴随脂质提取的孔隙形成：类似去污剂的机制。2.在明显弯曲的膜中迅速形成的大孔：破裂。因此，我们观察到三种孔隙形成模式(环形孔隙形成，脂质提取，和破裂）取决于肽浓度和局部排列。这些观察结果与实验观察结果和假设的蜂毒素模式一致。通过这项研究,我们发现蜂毒肽的局部排列和种群以及膜变形的面积扩展速率是多种孔形成机制启动和竞争的关键。
