Water, protons, and ions biomolecular systems

水、质子和离子生物分子系统

• 批准号: 7734025
• 负责人: Gerhard Hummer
• 金额: $ 28.7万
• 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/7734025
• 关键词: Active Sites; Aerobic; Affect; Austria; Back; Bacteria; Bathing; Behavior; Binding; Biological; Biological Process; Cells; Charge; Collaborations; Condition; Crowding; Devices; Diffusion; Dimensions; Electrons; Elements; Ensure; Environment; Enzymes; Equilibrium; Exhibits; Extravasation; Finland; Glutamic Acid; Goals; Hydrogen Bonding; Institutes; Investigation; Ions; Length; Life; Liquid substance; Maine; Mediating; Mediation; Mediator of activation protein; Membrane; Mitochondria; Modeling; Molecular; National Institute of Diabetes and Digestive and Kidney Diseases; Organelles; Oxygen; Pathway interactions; Physiological; Play; Positioning Attribute; Process; Production; Property; Proteins; Proton Pump; Protons; Pump; Range; Reaction; Respiratory Chain; Role; Solvents; System; Texas; Time; Transport Process; Tube; United States National Institutes of Health; Universities; Water; austin; base; cytochrome c oxidase; density; design; expectation; molecular dynamics; nanochannel; nanofluidic; novel; preconditioning; prevent; protein folding; protonation; simulation; theories; water channel; water flow

Water plays a central role in the stability, dynamics, and function of biomolecules. 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. 1D water wires: In collaboration with Drs. Dellago and Kofinger from the University of Vienna, Austria, we performed studies of one-dimensional water wires. Such wires are important elements of biological water channels and proton conduction wires in proteins. We showed that a dipole lattice model accurately recovers key properties of 1D confined water when compared to atomically detailed simulations. In a major reduction in computational complexity, we represented the dipole model in terms of effective Coulombic charges, which allowed us to study pores of macroscopic lengths in equilibrium with a water bath. At ambient conditions, the water chains filling the tube are essentially continuous up to macroscopic dimensions. In the filled state, the chains of water molecules in the tube remain dipole-ordered up to macroscopic lengths of 0.1 mm, and the dipolar order is estimated to persist for times up to 0.1 s. The observed dipolar order in continuous water chains is a precondition for the use of nanoconfined 1D water as mediator of fast long-range proton transport in proteins and fuel cells. Water in nanoconfinement: In collaboration with Prof. Garde (Rensselaer Polytechnic Institute) and Prof. Rasaiah (University of Maine), we have explored the highly unusual properties of water molecules confined to nonpolar pores and cavities of nanoscopic dimensions. Water filling of these molecularly tight spaces is strongly cooperative, resulting in the possible coexistence of filled and empty states and sensitivity to tiny perturbations of the pore polarity and solvent conditions. Confined water molecules form tightly hydrogen-bonded wires or clusters. Weak attractions to the confining wall and strong interactions between water molecules permit exceptionally rapid water flow, exceeding expectations from macroscopic hydrodynamics by several orders of magnitude. The proton mobility along 1D water wires also substantially exceeds that in the bulk. Proteins appear to 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). The unusual properties of water in nonpolar confinement are also relevant to the design of novel nanofluidic and molecular separation devices or fuel cells. Function of cytochrome c oxidase. Aerobic life is based on a molecular machinery that utilizes oxygen as a terminal electron sink. The membrane-bound cytochrome c oxidase (CcO) catalyzes the reduction of oxygen to water in mitochondria and many bacteria. The energy released in this reaction is conserved by pumping protons across the mitochondrial or bacterial membrane, creating an electrochemical proton gradient that drives production of ATP. In collaboration with Drs. Kaila and Wikstrom (University of Helsinki, Finland) we explored by molecular dynamics simulations how the protons pumped by CcO are prevented from flowing backwards during the process. We found that a conserved glutamic acid 242 near the active site of CcO undergoes a protonation state-dependent conformational change, which provides a valve in the pumping mechanism. The valve ensures that at any point in time, the proton pathway across the membrane is effectively discontinuous, thereby preventing thermodynamically favorable proton back-leakage while maintaining an overall high efficiency of proton translocation. Suppression of proton leakage is particularly important in mitochondria under physiological conditions, where production of ATP takes place in the presence of a high electrochemical proton gradient. Molecular transport in nanochannels: The cell provides a highly crowded environment. This crowding strongly affects the diffusive dynamics of biomolecules. However, we are still lacking a theory of diffusion in crowded environments. In collaboration with Dr. Mittal (NIDDK, NIH) and Dr. Truskett (University of Texas at Austin), we studied the diffusive dynamics of a fluid in the confined between parallel smooth hard walls. We found an unexpected correlation between the position-dependent diffusion coefficient normal to the walls and the local packing density. We could explain this positive correlation by the fact that for repulsion-dominated fluids high density regions also have the largest available volume, consistent with the observed fast local diffusivity. Importantly, we confirmed that the diffusion coefficients strongly deviate from bulk fluid behavior, making corrections necessary in studies of diffusion in crowded environments like those of cells and their organelles.

水在生物分子的稳定性、动力学和功能中起着核心作用。 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。 1D水管：我们与奥地利维也纳大学的Dellago和Kofinger博士合作，对一维水线进行了研究。 这种导线是生物水通道和蛋白质中质子传导导线的重要元素。 我们表明，偶极晶格模型准确地恢复了一维承压水的关键属性相比，原子详细的模拟。在一个主要的计算复杂性降低，我们表示的偶极子模型的有效库仑电荷，这使我们能够研究与水浴平衡的宏观长度的孔。在环境条件下，填充管的水链基本上连续到宏观尺寸。在填充状态下，管中的水分子链保持偶极有序，直到0.1 mm的宏观长度， 估计偶极序持续时间高达0.1秒。在连续水链中观察到的偶极顺序是使用纳米限制的一维水作为快速介体的先决条件。 蛋白质和燃料电池中的长距离质子传输。 纳米限制中的水：在与Garde教授（伦斯勒理工学院）和Rasaiah教授（缅因州大学）的合作中，我们探索了水分子局限于非极性孔和纳米尺度空腔中的极不寻常的性质。水填充这些分子紧密的空间是强烈的合作，导致填充和空状态的可能共存，并对孔极性和溶剂条件的微小扰动敏感。受限的水分子形成紧密的氢键线或簇。弱吸引力的限制壁和水分子之间的强烈相互作用允许异常快速的水流，超过预期的宏观流体力学的几个数量级。质子迁移率沿着一维水线也大大超过了在体。蛋白质似乎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门控质子泵和酶中的质子流）。水在非极性限制中的不寻常性质也与新型纳米流体和分子分离装置或燃料电池的设计有关。 细胞色素c氧化酶的功能。有氧生活是基于一种分子机制，利用氧气作为终端电子汇。膜结合细胞色素c氧化酶（CcO）催化线粒体和许多细菌中的氧还原为水。这里面释放的能量 通过泵送质子穿过线粒体或细菌膜，产生驱动ATP产生的电化学质子梯度，反应得以保存。在与Kaila和Wikstrom博士（芬兰赫尔辛基大学）的合作中，我们通过分子动力学模拟探索了如何防止CcO泵送的质子在该过程中倒流。 我们发现，一个保守的谷氨酸242附近的活性位点的CcO经历了质子化状态依赖的构象变化，这提供了一个阀门的泵送机制。该阀门确保在任何时间点，跨膜的质子路径实际上是不连续的，从而防止热力学有利的质子回漏，同时保持质子移位的整体高效率。抑制 在生理条件下，在线粒体中质子泄漏的发生是特别重要的，其中ATP的产生在高电化学质子梯度的存在下发生。 纳米通道中的分子运输：细胞提供了一个高度拥挤的环境。 这种拥挤强烈影响生物分子的扩散动力学。 然而，我们仍然缺乏在拥挤环境中的扩散理论。 在与Mittal博士（NIDDK，NIH）和Truskett博士（德克萨斯大学奥斯汀分校）的合作中，我们研究了平行光滑硬壁之间的流体扩散动力学。 我们发现垂直于壁的位置相关扩散系数与局部堆积密度之间存在意想不到的相关性。 我们可以解释这种正相关性的事实，排斥为主的流体高密度区域也有最大的可用体积，与观察到的快速局部扩散。重要的是，我们证实了扩散系数强烈偏离体相流体行为，在拥挤的环境中，如细胞及其细胞器中的扩散研究中需要进行校正。