Cell membranes act as semi-permeable barriers, often restricting the entry of large or hydrophilic molecules. Nonetheless, certain amphiphilic molecules, such as antimicrobial and cell-penetrating peptides, can cross these barriers. In this study, we demonstrate that specific properties of transmembrane proteins/peptides can enhance membrane permeation of amphiphilic peptides. Using coarse-grained molecular dynamics with free-energy calculations, we identify key translocation-enhancing attributes of transmembrane proteins/peptides: a continuous hydrophilic patch, charged residues preferably in the membrane center, and aromatic hydrophobic residues. By employing both coarse-grained and atomistic simulations, complemented by experimental validation, we show that these properties not only enhance peptide translocation but also speed up lipid flip-flop. The enhanced flip-flop reinforces the idea that proteins such as scramblases and insertases not only share structural features but also operate through identical biophysical mechanisms enhancing the insertion and translocation of amphiphilic molecules. Our insights offer guidelines for the designing of translocation-enhancing proteins/peptides that could be used in medical and biotechnological applications.

中文翻译：

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优化易位增强跨膜蛋白的特性

细胞膜充当半渗透屏障，通常限制大分子或亲水分子的进入。尽管如此，某些两亲分子，例如抗菌肽和细胞穿透肽，可以跨越这些屏障。在这项研究中，我们证明跨膜蛋白/肽的特定性质可以增强两亲性肽的膜渗透。利用粗粒度分子动力学和自由能计算，我们确定了跨膜蛋白/肽的关键易位增强属性：连续的亲水性斑块、优选位于膜中心的带电残基和芳香族疏水残基。通过采用粗粒度和原子模拟，并辅以实验验证，我们表明这些特性不仅增强了肽易位，而且还加速了脂质翻转。增强的触发器强化了这样的想法，即诸如扰乱酶和插入酶之类的蛋白质不仅具有相同的结构特征，而且还通过相同的生物物理机制来增强两亲性分子的插入和易位。我们的见解为设计可用于医学和生物技术应用的易位增强蛋白质/肽提供了指导。