Maia Raiza, Ataka Kenichi, Heberle Joachim, Baiz Carlos R
Department of Chemistry, University of Texas at Austin, 105 E 24th St. A5300, Austin, Texas 78712, United States.
Department of Physics, Freie Universität Berlin, Arnimallee 14, 14195 Berlin, Germany.
J Phys Chem B. 2025 May 1;129(17):4123-4132. doi: 10.1021/acs.jpcb.5c00225. Epub 2025 Apr 18.
The pH Low Insertion Peptide (pHLIP) is a useful model for exploring the biophysical chemistry of pH-driven membrane insertion and folding. This review discusses recent advancements in understanding the molecular mechanisms underlying pHLIP behavior, focusing on its ability to transition from a soluble, unstructured state to a membrane-inserted α-helix. Protonation of acidic residues, changes in peptide hydrophobicity, and interactions with the lipid bilayer, are described. Recent studies using NMR, infrared spectroscopy, and molecular dynamics simulations have provided a stepwise mechanistic model of the coupled folding and insertion process including its intermediate states present under different pH conditions. In addition, pHLIP ability to selectively target acidic microenvironments, such as those found in tumors, has made it a promising tool for biomedical applications. We provide an overview of recent fundamental studies and applications and discuss how future work can benefit from combining advanced experimental and computational approaches to refine our understanding of the peptide's structure-function relationships.
pH低插入肽（pHLIP）是探索pH驱动的膜插入和折叠生物物理化学的有用模型。本综述讨论了在理解pHLIP行为背后分子机制方面的最新进展，重点关注其从可溶性、无结构状态转变为膜插入α螺旋的能力。描述了酸性残基的质子化、肽疏水性的变化以及与脂质双层的相互作用。最近使用核磁共振、红外光谱和分子动力学模拟的研究提供了一个耦合折叠和插入过程的逐步机制模型，包括在不同pH条件下存在的中间状态。此外，pHLIP选择性靶向酸性微环境（如肿瘤中发现的微环境）的能力使其成为生物医学应用中有前景的工具。我们概述了最近的基础研究和应用，并讨论了未来的工作如何通过结合先进的实验和计算方法来改进我们对该肽结构-功能关系的理解而受益。
