Department of Physics, North Dakota State University , Fargo, North Dakota 58108, United States.
Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
ACS Nano. 2017 Mar 28;11(3):2858-2871. doi: 10.1021/acsnano.6b07981. Epub 2017 Mar 17.
At physiological conditions, most proteins or peptides can fold into relatively stable structures that present on their molecular surfaces specific chemical patterns partially smeared out by thermal fluctuations. These nanoscopically defined patterns of charge, hydrogen bonding, and/or hydrophobicity, along with their elasticity and shape stability (folded proteins have Young's moduli of ∼1 × 10 Pa), largely determine and limit the interactions of these molecules, such as molecular recognition and allosteric regulation. In this work, we show that the membrane-permeating activity of antimicrobial peptides (AMPs) and cell-penetrating peptides (CPPs) can be significantly enhanced using prototypical peptides with "molten" surfaces: metaphilic peptides with quasi-liquid surfaces and adaptable shapes. These metaphilic peptides have a bottlebrush-like architecture consisting of a rigid helical core decorated with mobile side chains that are terminated by cationic or hydrophobic groups. Computer simulations show that these flexible side chains can undergo significant rearrangement in response to different environments, giving rise to adaptable surface chemistry of the peptide. This quality makes it possible to control their hydrophobicity over a broad range while maintaining water solubility, unlike many AMPs and CPPs. Thus, we are able to show how the activity of these peptides is amplified by hydrophobicity and cationic charge, and rationalize these results using a quantitative mean-field theory. Computer simulations show that the shape-changing properties of the peptides and the resultant adaptive presentation of chemistry play a key enabling role in their interactions with membranes.
在生理条件下，大多数蛋白质或肽可以折叠成相对稳定的结构，这些结构在其分子表面呈现出特定的化学模式，部分被热波动模糊。这些纳米级的电荷、氢键和/或疏水性分布模式，以及它们的弹性和形状稳定性（折叠蛋白的杨氏模量约为 1×10 Pa），在很大程度上决定和限制了这些分子的相互作用，如分子识别和变构调节。在这项工作中，我们表明，使用具有“熔融”表面的典型肽，可以显著增强抗菌肽（AMPs）和细胞穿透肽（CPPs）的膜透活性：具有准液相和可适应形状的亲液肽。这些亲液肽具有瓶刷状结构，由刚性螺旋核心和带有可移动侧链的阳离子或疏水性基团组成。计算机模拟表明，这些柔性侧链可以根据不同的环境发生显著的重排，从而赋予肽可适应的表面化学性质。这种性质使其能够在保持水溶性的同时，在广泛的范围内控制其疏水性，这与许多 AMPs 和 CPPs 不同。因此，我们能够展示这些肽的活性如何通过疏水性和阳离子电荷得到增强，并使用定量平均场理论来合理化这些结果。计算机模拟表明，肽的形状变化特性和由此产生的化学适应性呈现对于它们与膜的相互作用起着关键的作用。
