Pomès Régis, Roux Benoît
Structural Biology and Biochemistry, Hospital for Sick Children, and Department of Biochemistry, University of Toronto, Toronto, Ontario M5G 1X8, Canada.
Biophys J. 2002 May;82(5):2304-16. doi: 10.1016/S0006-3495(02)75576-8.
The conduction of protons in the hydrogen-bonded chain of water molecules (or "proton wire") embedded in the lumen of gramicidin A is studied with molecular dynamics free energy simulations. The process may be described as a "hop-and-turn" or Grotthuss mechanism involving the chemical exchange (hop) of hydrogen nuclei between hydrogen-bonded water molecules arranged in single file in the lumen of the pore, and the subsequent reorganization (turn) of the hydrogen-bonded network. Accordingly, the conduction cycle is modeled by two complementary steps corresponding respectively to the translocation 1) of an ionic defect (H+) and 2) of a bonding defect along the hydrogen-bonded chain of water molecules in the pore interior. The molecular mechanism and the potential of mean force are analyzed for each of these two translocation steps. It is found that the mobility of protons in gramicidin A is essentially determined by the fine structure and the dynamic fluctuations of the hydrogen-bonded network. The translocation of H+ is mediated by spontaneous (thermal) fluctuations in the relative positions of oxygen atoms in the wire. In this diffusive mechanism, a shallow free-energy well slightly favors the presence of the excess proton near the middle of the channel. In the absence of H+, the water chain adopts either one of two polarized configurations, each of which corresponds to an oriented donor-acceptor hydrogen-bond pattern along the channel axis. Interconversion between these two conformations is an activated process that occurs through the sequential and directional reorientation of water molecules of the wire. The effect of hydrogen-bonding interactions between channel and water on proton translocation is analyzed from a comparison to the results obtained previously in a study of model nonpolar channels, in which such interactions were missing. Hydrogen-bond donation from water to the backbone carbonyl oxygen atoms lining the pore interior has a dual effect: it provides a coordination of water molecules well suited both to proton hydration and to high proton mobility, and it facilitates the slower reorientation or turn step of the Grotthuss mechanism by stabilizing intermediate configurations of the hydrogen-bonded network in which water molecules are in the process of flipping between their two preferred, polarized states. This mechanism offers a detailed molecular model for the rapid transport of protons in channels, in energy-transducing membrane proteins, and in enzymes.
利用分子动力学自由能模拟研究了嵌入短杆菌肽A内腔的水分子氢键链（或“质子线”）中质子的传导。该过程可描述为“跳跃-翻转”或Grotthuss机制，涉及排列在孔内腔单排的氢键水分子之间氢核的化学交换（跳跃），以及随后氢键网络的重新排列（翻转）。因此，传导循环由两个互补步骤建模，分别对应于1）离子缺陷（H+）和2）键合缺陷沿孔内部水分子氢键链的易位。对这两个易位步骤中的每一个进行了分子机制和平均力势分析。发现短杆菌肽A中质子的迁移率基本上由氢键网络的精细结构和动态波动决定。H+的易位由质子线中氧原子相对位置的自发（热）波动介导。在这种扩散机制中，一个浅的自由能阱略微有利于通道中部附近存在过量质子。在没有H+的情况下，水链采用两种极化构型中的一种，每种构型对应于沿通道轴的定向供体-受体氢键模式。这两种构象之间的相互转化是一个活化过程，通过质子线水分子的顺序和定向重新取向发生。通过与先前在模型非极性通道研究中获得的结果进行比较，分析了通道与水之间的氢键相互作用对质子易位的影响，在该研究中不存在这种相互作用。水向孔内部衬里的主链羰基氧原子的氢键供体具有双重作用：它提供了一种既适合质子水合又适合高质子迁移率的水分子配位，并且通过稳定氢键网络的中间构型促进了Grotthuss机制中较慢的重新取向或翻转步骤，在该构型中水分子正在其两个优选的极化状态之间翻转。该机制为通道、能量转换膜蛋白和酶中质子的快速运输提供了详细的分子模型。
