Characterizing the Molecular Mechanisms for Flipping Charged Peptide Flanking Loops across a Lipid Bilayer
Characterizing the Molecular Mechanisms for Flipping Charged Peptide Flanking Loops across a Lipid Bilayer
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DOI：
10.1021/acs.jpcb.8b06613
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发表时间：
2018-11-15
影响因子：
3.3
通讯作者：
Van Lehn, Reid C.
中科院分区：
文献类型：
--
作者：
Patel, Samarthaben J.;Van Lehn, Reid C.
细胞膜在很大程度上阻止了带电分子的被动扩散，因为与带电基团跨疏水脂质双层核心的转移相关的巨大自由能障碍。尽管有这一障碍，一些多肽可以通过以惊人的速度在第二分钟的时间尺度上翻转带电的侧翼环，在跨膜和表面吸附状态之间进行相互转换。一些多跨膜蛋白的跨膜螺旋经历了类似的重定位过程，这表明环翻转可能是调节膜蛋白拓扑的一种机制；然而，这种行为背后的分子机制尚不清楚。在这项工作中，我们研究了具有疏水跨膜螺旋、带电侧翼环和中心暴露的不同质子化状态的天冬氨酸残基的多肽所表现出的环翻转行为。我们利用全原子温度加速分子动力学模拟来预测环翻转的可能性，而不预先定义特定的环翻转路径。我们证明，这种方法可以识别多种可能的翻转途径，每条途径的流行程度取决于中心残基的质子化状态。特别是，我们发现带电的中心残基通过稳定膜水缺陷促进了环翻转，使电荷转移能够“自催化”。这些发现在分子水平上提供了对带电翻转途径的详细了解，这些途径可能推广到其他电荷转移过程，如脂类触发器或多跨膜蛋白的大规模构象重排。
The cell membrane largely prevents the passive diffusion of charged molecules due to the large free energy barrier associated with translocating charged groups across the hydrophobic lipid bilayer core. Despite this barrier, some peptides can interconvert between transmembrane and surface-adsorbed states by "flipping" charged flanking loops across the bilayer on a surprisingly rapid second-minute time scale. The transmembrane helices of some multispanning membrane proteins undergo similar reorientation processes, suggesting that loop-flipping may be a mechanism for regulating membrane protein topology; however, the molecular mechanisms underlying this behavior remain unknown. In this work, we study the loop-flipping behavior exhibited by a peptide with a hydrophobic transmembrane helix, charged flanking loops, and a central, membrane-exposed aspartate residue of varying protonation state. We utilize all-atom temperature accelerated molecular dynamics simulations to predict the likelihood of loop-flipping without predefining specific loop-flipping pathways. We demonstrate that this approach can identify multiple possible flipping pathways, with the prevalence of each pathway depending on the protonation state of the central residue. In particular, we find that a charged central residue facilitates loop-flipping by stabilizing membrane water defects, enabling the "self-catalysis" of charge translocation. These findings provide detailed molecular-level insights into charged loop-flipping pathways that may generalize to other charge translocation processes, such as lipid flip-flop or the large-scale conformational rearrangements of multispanning membrane proteins.