The Szeto-Schiller (SS) peptides are a subclass of cell-penetrating peptides that can specifically target mitochondria and mediate conditions caused by mitochondrial dysfunction. In this work, we constructed an iron-chelating SS peptide and studied its interaction with a mitochondrial-mimicking membrane using atomistic molecular dynamics (MD) simulations. We report that the peptide/membrane interaction is thermodynamically favorable, and the localization of the peptide to the membrane is driven by electrostatic interactions between the cationic residues and the anionic phospholipid headgroups. The insertion of the peptide into the membrane is driven by hydrophobic interactions between the aromatic side chains in the peptide and the lipid acyl tails. We also probed the translocation of the peptide across the membrane by applying nonequilibrium steered MD simulations and resolved the translocation pathway, free energy profile, and metastable states. We explored four distinct orientations of the peptide along the translocation pathway and found that one orientation was energetically more favorable than the other orientations. We tested a significantly slower pulling velocity on the most thermodynamically favorable system and compared metastable states during peptide translocation. We found that the peptide can optimize hydrophobic interactions with the membrane by having aromatic side chains interacting with the lipid acyl tails instead of forming π–π interactions with each other. The mechanistic insights emerging from our work will potentially facilitate improved peptide design with enhanced activity.

中文翻译：

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靶向线粒体膜的生物共轭肽的相互作用和运输

司托-席勒 (SS) 肽是细胞穿透肽的一个亚类，可以特异性靶向线粒体并介导由线粒体功能障碍引起的病症。在这项工作中，我们构建了一种铁螯合 SS 肽，并使用原子分子动力学 (MD) 模拟研究了它与模拟线粒体膜的相互作用。我们报告说，肽/膜相互作用在热力学上是有利的，并且肽在膜上的定位是由阳离子残基和阴离子磷脂头基之间的静电相互作用驱动的。肽插入膜是由肽中的芳香族侧链和脂酰基尾部之间的疏水相互作用驱动的。我们还通过应用非平衡引导MD模拟来探测肽跨膜易位，并解析了易位途径、自由能谱和亚稳态。我们沿着易位途径探索了肽的四种不同方向，发现一种方向比其他方向在能量上更有利。我们在热力学最有利的系统上测试了明显较慢的牵引速度，并比较了肽易位期间的亚稳态。我们发现，该肽可以通过使芳香族侧链与脂酰基尾部相互作用而不是彼此形成π-π相互作用来优化与膜的疏水相互作用。我们工作中产生的机制见解将有可能促进改进肽设计并增强活性。