Water, protons, and ions biomolecular systems

水、质子和离子在生物分子的稳定性、动力学和功能中起着核心作用，也是药物分子结合的重要因素(1)。通过疏水效应和氢键相互作用，水是蛋白质折叠的主要因素。在许多酶中，它直接参与催化功能。特别是，蛋白质内部的水经常介导质子在溶剂介质和活性位点之间的转移。这种水通常被限制在相对非极性的孔隙和纳米尺度的空腔中，表现出非常不寻常的性质，如高水迁移率，高质子电导率，或在充满和空状态之间的急剧转变。蛋白质利用封闭水的这些不寻常的特性来发挥其生物功能，例如，确保水通道蛋白中的水快速流动，或控制质子泵和酶中的质子流动。水是结合和识别过程中的关键因素(2)，并决定了纳米尺度上的摩擦(3)。我们在水、质子和离子与蛋白质功能相关的领域取得了许多进展。

Water, protons, and ions play a central role in the stability, dynamics, and function of biomolecules, and are also an important factor in the binding of drug molecules (1). Through the hydrophobic effect and hydrogen bond interactions, water is a major factor in the folding of proteins. In many enzymes, it participates directly in the catalytic function. In particular, water in the protein interior often mediates the transfer of protons between the solvent medium and the active site. Such water, often confined into relatively nonpolar pores and cavities of nanoscopic dimensions, exhibits highly unusual properties, such as high water mobility, high proton conductivity, or sharp transitions between filled and empty states. Proteins exploit these unusual properties of confined water in their biological function, e.g., to ensure rapid water flow in aquaporins, or to gate proton flow in proton pumps and enzymes. Water is a key factor in the binding and recognition process (2), and determines the friction at the nanoscale (3). We have made a number of advances in areas where water, protons, and ions are connected to protein function. Ion channel gating. Nerve signaling in humans and chemical sensing in bacteria both rely on the controlled opening and closing of the ion-conducting pore in pentameric ligand-gated ion channels. With the help of a multiscale simulation approach that combined a low-resolution elastic model with atomistic molecular dynamics simulations, we studied the opening and closing of the pore in GLIC, a prokaryotic channel (4). We found that the pore closes in an iris-like fashion, with the pore-lining helices collectively tilting with respect to the membrane normal. This motion induces a cooperative drying transition of the channel pore, in which the water rapidly exits from its central nonpolar region. The mechanical work of opening the pore is performed primarily on the M2-M3 loop. Strong interactions of this short and conserved loop with the extracellular domain are therefore crucial to couple ligand binding to channel opening. Interior hydration of proteins. We used simulations to resolve a long-standing question in protein-water interactions: whether the nonpolar cavity in the protein interleukin-1β is filled by water or empty (5). With the help of molecular dynamics simulations, we studied the thermodynamics of filling the central nonpolar cavity and the four polar cavities of interleukin-1β. We found that water in the central nonpolar cavity is thermodynamically unstable, independent of simulation force field and water model. The apparent reason is the relatively small size of the cavity, with a volume less than 80 cubic Angstrom. Our results are consistent with the most recent X-ray crystallographic and simulation studies, but disagree with an earlier interpretation of nuclear magnetic resonance (NMR) experiments probing protein-water interactions. To resolve this apparent discrepancy we showed that the measured nuclear Overhauser effects can, in all likelihood, be attributed to interactions with buried and surface water molecules near the cavity. Our study thus resolves the long-standing controversy concerning the presence of water in interleukin-1β. Single-file water as a proton wire. With a quantum mechanical description we studied the transfer of protons along an ordered chain of water molecules (6). Such water chains have highly unusual properties, including a strong dipolar order (7). We found that for short water chains with four water molecules, the proton transfer reaction is semi-concerted. We also showed that the barrier of the pT reaction depends linearly on the proton affinity of the donor but is nearly independent of the proton affinity of the acceptor, corresponding to Bronsted slopes of one and zero, respectively. These simulations provide a detailed picture of an essential step in many biochemical reactions. 1. G. Hummer, Molecular binding: under waters influence, Nature Chemistry 2, 906-907 (2010). 2. J. Mittal, G. Hummer, Interfacial thermodynamics of confined water near molecularly rough surfaces, Faraday Discuss. 146, 341-352 (2010). 3. A. Kalra, S. Garde, G. Hummer, Lubrication by molecularly thin water films confined between nanostructured membranes, Eur. Phys. J. Special Topics 189, 147-154 (2010). 4. F. Zhu, G. Hummer, Pore opening and closing of a pentameric ligand-gated ion channel, Proc. Natl. Acad. Sci. USA 107, 19814-19819 (2010). 5. H. Yin, G. Feng, G. M. Clore, G. Hummer, J. C. Rasaiah, Water in the polar and nonpolar cavities of the protein interleukin-1β, J. Phys. Chem. B 114, 16290-16297 (2010) 6. V. R. I. Kaila, G. Hummer, Energetics and dynamics of proton transfer reactions along short water wires, Phys. Chem. Chem. Phys. 13, 13207-13215 (2011). 7. J. Kfinger, G. Hummer, C. Dellago, Single-file water in nanopores, Phys. Chem. Chem. Phys. 13, 15403 - 15417 (2011).