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。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。具体地说，蛋白质内部的水经常调节质子在溶剂介质和活性中心之间的转移。这种水通常被限制在相对非极性的纳米尺度的孔和腔中，表现出非常不寻常的性质，如高水流动性、高质子传导性，或者在填充状态和空状态之间的急剧转变。蛋白质在生物功能中利用承压水的这些不同寻常的特性，例如，确保水在水通道中的快速流动，或在质子泵和酶中开启质子流动。水是结合和识别过程中的关键因素(2)，并决定纳米级的摩擦力(3)。我们在水、质子和离子与蛋白质功能相关的领域取得了一些进展。 离子通道门控。人类的神经信号和细菌的化学感觉都依赖于五聚体配基门控离子通道中离子传导孔的受控打开和关闭。借助低分辨率弹性模型和原子分子动力学模拟相结合的多尺度模拟方法，我们研究了原核生物通道GLIC中孔的打开和关闭(4)。我们发现，毛孔以虹膜状的方式闭合，毛孔衬里螺旋相对于膜法线集体倾斜。这一运动导致了孔道孔隙的协同干燥转变，其中水迅速从其中心非极区退出。开孔的机械功主要在M2-M3环上执行。因此，这个短而保守的环与细胞外域的强烈相互作用对于将配体结合到通道开放是至关重要的。 蛋白质的内部水合作用。我们使用模拟来解决蛋白质-水相互作用中的一个长期存在的问题：蛋白质白介素1中的非极性空腔是被水填满还是空的。借助于分子动力学模拟，我们研究了白介素1的中心非极空腔和四个极空腔填充的热力学。我们发现，中心非极空腔中的水是热力学不稳定的，与模拟力场和水模型无关。明显的原因是腔的体积相对较小，体积不到80立方埃。我们的结果与最新的X射线结晶学和模拟研究一致，但与早期对探测蛋白质-水相互作用的核磁共振实验的解释不一致。为了解决这一明显的差异，我们表明，测量到的核Overhauser效应很可能归因于与洞穴附近的埋藏和地表水分子的相互作用。因此，我们的研究解决了长期存在的关于白介素1中是否存在水的争议。 单列水作为质子线。利用量子力学描述，我们研究了质子沿有序水分子链的转移(6)。这种水链具有非常不寻常的性质，包括强烈的偶极有序(7)。我们发现，对于含有四个水分子的短水链，质子转移反应是半协同的。我们还发现，PT反应的势垒线性地依赖于给体的质子亲和力，但几乎与受体的质子亲和力无关，对应的Bronsted斜率分别为1和0。这些模拟提供了许多生化反应中必不可少的一步的详细画面。 1.G.悍马，《分子结合：在水的影响下》，《自然化学》2,906-907(2010)。 2.J.Mittal，G.Hummer，《分子粗糙表面附近承压水的界面热力学》，Faraday讨论。146,341-352(2010)。 3.A.Kalra，S.Garde，G.Hummer，《限制在纳米结构膜之间的分子薄水膜的润滑》，EUR。太棒了。J.特别专题189,147-154(2010年)。 4.朱福荣，G.Hummer，五聚体配基门控离子通道的开孔与闭孔，Proc.娜塔莉。阿卡德。SCI。美国第107,19814-19819(2010年)。 5.尹海文、冯国荣、克洛尔、休默、拉赛亚，蛋白质白介素1的极腔和非极腔中的水，J.Phys。化学。B114,16290-16297(2010年) 6.V.R.I.Kaila，G.Hummer，沿短水线的质子转移反应的能量学和动力学，物理。化学。化学。太棒了。13,13207-13215(2011年)。 7.J.Kinger，G.Hummer，C.Dellago，单列纳米孔中的水，Phys.化学。化学。太棒了。13,15403-15417(2011年)。

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).