Hub Jochen S, Grubmüller Helmut, de Groot Bert L
Computational Biomolecular Dynamics Group, Max-Planck-Institute for Biophysical Chemistry, Am Fassberg 11, Göttingen, 37077, Germany.
Handb Exp Pharmacol. 2009(190):57-76. doi: 10.1007/978-3-540-79885-9_3.
Aquaporins (AQPs) are a family of integral membrane proteins, which facilitate the rapid and yet highly selective flux of water and other small solutes across biological membranes. Molecular dynamics (MD) simulations contributed substantially to the understanding of the molecular mechanisms that underlie this remarkable efficiency and selectivity of aquaporin channels. This chapter reviews the current state of MD simulations of aquaporins and related aquaglyceroporins as well as the insights these simulations have provided. The mechanism of water permeation through AQPs and methods to determine channel permeabilities from simulations are described. Protons are strictly excluded from AQPs by a large electrostatic barrier and not by an interruption of the Grotthuss mechanism inside the pore. Both the protein's electric field and desolvation effects contribute to this barrier. Permeation of apolar gas molecules such as CO(2) through AQPs is accompanied by a large energetic barrier and thus can only be expected in membranes with a low intrinsic gas permeability. Additionally, the insights from simulations into the mechanism of glycerol permeation through the glycerol facilitator GlpF from E. coli are summarized. Finally, MD simulations are discussed that revealed that the aro-matic/arginine constriction region is generally the filter for uncharged solutes, and that AQP selectivity is controlled by a hydrophobic effect and steric restraints.
水通道蛋白（AQPs）是一类整合膜蛋白家族，可促进水和其他小分子溶质快速且高度选择性地穿过生物膜。分子动力学（MD）模拟对理解水通道蛋白通道这种显著效率和选择性背后的分子机制做出了重大贡献。本章综述了水通道蛋白和相关水甘油通道蛋白的MD模拟现状以及这些模拟所提供的见解。描述了水通过水通道蛋白的渗透机制以及从模拟中确定通道渗透率的方法。质子通过一个大的静电屏障被严格排除在水通道蛋白之外，而不是通过孔内质子跳跃机制的中断。蛋白质的电场和去溶剂化效应都对这个屏障有贡献。诸如二氧化碳等非极性气体分子通过水通道蛋白的渗透伴随着一个很大的能量屏障，因此只有在固有气体渗透率低的膜中才可能发生。此外，总结了模拟对甘油通过大肠杆菌甘油转运蛋白GlpF的渗透机制的见解。最后，讨论了MD模拟，这些模拟揭示芳香族/精氨酸收缩区通常是不带电溶质的过滤器，并且水通道蛋白的选择性受疏水效应和空间限制的控制。
