We present relative binding free energy calculations for six antimicrobial peptide–micelle systems, three peptides interacting with two types of micelles. The peptides are the scorpion derived antimicrobial peptide (AMP), IsCT and two of its analogues. The micelles are dodecylphosphatidylcholine (DPC) and sodium dodecylsulphate (SDS) micelles. The interfacial electrostatic properties of DPC and SDS micelles are assumed to be similar to those of zwitterionic mammalian and anionic bacterial membrane interfaces, respectively. We test the hypothesis that the binding strength between peptides and the anionic micelle SDS can provide information on peptide antimicrobial activity, since it is widely accepted that AMPs function by binding to and disrupting the predominantly anionic lipid bilayer of the bacterial cytoplasmic membrane. We also test the hypothesis that the binding strength between peptides and the zwitterionic micelle DPC can provide information on peptide haemolytic activities, since it is accepted that they also bind to and disrupt the zwitterionic membrane of mammalian cells. Equilibrium structures of the peptides, micelles and peptide–micelle complexes are obtained from more than 300 ns of molecular dynamics simulations. A thermodynamic cycle is introduced to compute the binding free energy from electrostatic, non-electrostatic and entropic contributions. We find relative binding free energy strengths between peptides and SDS to correlate with the experimentally measured rankings for peptide antimicrobial activities, and relative free energy binding strengths between peptides and DPC to correlate with the observed rankings for peptide haemolytic toxicities. These findings point to the importance of peptide–membrane binding strength for antimicrobial activity and haemolytic activity.

中文翻译：

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抗菌肽与 SDS 或 DPC 胶束之间的相对结合自由能

我们提出了六种抗菌肽-胶束系统的相对结合自由能计算，三种肽与两种类型的胶束相互作用。这些肽是源自蝎子的抗微生物肽 (AMP)、IsCT 及其两种类似物。胶束是十二烷基磷脂酰胆碱 (DPC) 和十二烷基硫酸钠 (SDS) 胶束。假设 DPC 和 SDS 胶束的界面静电特性分别类似于两性离子哺乳动物和阴离子细菌膜界面的静电特性。我们检验了肽与阴离子胶束 SDS 之间的结合强度可以提供有关肽抗菌活性的信息的假设，因为人们普遍认为 AMP 通过结合并破坏细菌细胞质膜的主要阴离子脂质双层来发挥作用。我们还测试了肽与两性离子胶束 DPC 之间的结合强度可以提供有关肽溶血活性的信息的假设，因为它们也可以结合并破坏哺乳动物细胞的两性离子膜。肽、胶束和肽-胶束复合物的平衡结构是从超过 300 ns 的分子动力学模拟中获得的。引入热力学循环来计算静电、非静电和熵贡献的结合自由能。我们发现肽和 SDS 之间的相对结合自由能强度与实验测量的肽抗菌活性排名相关，而肽和 DPC 之间的相对自由能结合强度与观察到的肽溶血毒性排名相关。