Water, protons, and ions biomolecular systems

水、质子和离子生物分子系统

• 批准号: 8349699
• 负责人: Gerhard Hummer
• 金额: $ 53.12万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8349699
• 关键词: Active Sites; Affinity; Area; Bacteria; Binding; Biochemical Reaction; Biological Process; Biology; Chemicals; Chemistry; Dimensions; Electron Transport; Ensure; Enzymes; Exhibits; Extracellular Domain; Film; Friction; Gated Ion Channel; Goals; Human; Hydration status; Hydrogen Bonding; Interleukin-1; Investigation; Ion Channel Gating; Ions; Iris; Ligand Binding; Ligands; Lubrication; Measures; Mechanics; Mediating; Mediation; Membrane; Modeling; Molecular; Motion; Nature; Nerve; Nuclear; Nuclear Magnetic Resonance; Pharmaceutical Preparations; Play; Process; Property; Proteins; Proton Pump; Protons; Reaction; Resolution; Respiratory Chain; Roentgen Rays; Role; Signal Transduction; Solvents; Surface; System; Thermodynamics; Water; Work; Yin; cytochrome c oxidase; interfacial; molecular dynamics; nanopore; nanoscale; nanostructured; protein folding; protein function; quantum; research study; simulation; water channel; water flow

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).

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）。 通过疏水作用和氢键相互作用，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，蛋白质内部的水通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，如高水流动性，高质子传导性，或填充和空状态之间的急剧转变。蛋白质在其生物功能中利用了承压水的这些不寻常的特性，例如，以确保水通道蛋白中的快速水流，或控制质子泵和酶中的质子流。 水是结合和识别过程中的关键因素（2），并决定了纳米级的摩擦力（3）。 我们已经在水、质子和离子与蛋白质功能相关的领域取得了许多进展。 离子通道门控。人类的神经信号和细菌的化学传感都依赖于五聚体配体门控离子通道中离子传导孔的受控打开和关闭。借助将低分辨率弹性模型与原子分子动力学模拟相结合的多尺度模拟方法，我们研究了原核通道GLIC中孔的打开和关闭（4）。 我们发现，孔关闭虹膜样的方式，与孔内衬螺旋集体倾斜相对于膜正常。 这种运动引起的通道孔隙，其中水迅速退出其中心非极性区域的合作干燥过渡。打开孔的机械功主要在M2-M3环上进行。因此，这种短而保守的环与细胞外结构域的强相互作用对于将配体结合与通道开放偶联是至关重要的。 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：蛋白质白细胞介素-1中的非极性空腔是由水填充还是空的（5）。 利用分子动力学模拟方法研究了白细胞介素-1填充中心非极性空穴和四个极性空穴的热力学过程。 我们发现中心非极性腔中水是不稳定的，与模拟力场和水模型无关。 明显的原因是腔的尺寸相对较小，体积小于80立方埃。 我们的研究结果与最新的X射线晶体学和模拟研究是一致的，但不同意早期的解释核磁共振（NMR）实验探测蛋白质-水的相互作用。为了解决这一明显的差异，我们表明，测得的核奥弗豪泽效应，在所有的可能性，是由于与埋在地下和表面水分子附近的空腔的相互作用。 因此，我们的研究解决了关于白细胞介素-1中水的存在的长期争议。 单行水作为质子线。 我们用量子力学描述研究了质子沿着有序的水分子链的转移（6）。 这种水链具有非常不寻常的性质，包括强偶极序（7）。我们发现，对于四个水分子的短水链，质子转移反应是半协调的。我们还表明，pT反应的障碍线性依赖于供体的质子亲和力，但几乎是独立的受体的质子亲和力，相应的布朗斯台德斜率分别为1和0。 这些模拟提供了许多生化反应中一个重要步骤的详细图像。 1. G. Hummer，Molecular binding：under沃茨influence，Nature Chemistry 2，906-907（2010）. 2. J.米塔尔湾胡明，分子粗糙表面附近承压水的界面热力学，法拉第讨论。146，341-352（2010）。 3. A.卡拉，S.加德湾Hummer，通过限制在纳米结构膜之间的分子薄水膜的润滑，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.克洛尔Hummer，J.C. Rasaiah，蛋白质白细胞介素-1的极性和非极性腔中的水，J. Phys. Chem. B 114，16290-16297（2010） 6. 诉R. I.凯拉湾Hummer，Energetics and dynamics of proton transfer reactions沿着着short water wires，Phys.Chem.Chem.Phys.13，13207-13215（2011）。 7. J. Kfinger，G. Hummer角Dellago，Single-file water in nanopores，Phys.Chem.Chem.Phys.13，15403 - 15417（2011）。