Water, protons, and ions biomolecular systems

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。 一维水线：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。这些线是蛋白质中生物水通道和质子传导线的重要元件。我们发现，与原子细节模拟相比，偶极格子模型准确地恢复了一维承压水的关键性质。在计算复杂性的大幅降低中，我们用有效库仑电荷来表示偶极模型，这使得我们能够研究宏观长度的毛孔在水浴中的平衡。在环境条件下，充满管子的水链基本上是连续的，直到宏观尺寸。在填充状态下，管子中的水分子链保持偶极有序，直到宏观长度为0.1 mm，并且 在连续水链中观察到的偶极序数是使用纳米承压一维水作为FAST介质的前提条件 蛋白质和燃料电池中的远程质子传输。 纳米限制中的水：我们与Rensselaer理工学院的Garde教授和缅因州大学的Rasaiah教授合作，探索了限制在纳米尺寸的非极性孔和空腔中的水分子的极不寻常的性质。这些分子紧密空间的水填充是强烈合作的，导致填充态和空态可能共存，并对孔极性和溶剂条件的微小扰动敏感。受限水分子形成紧密的氢键金属丝或团簇。对隔离墙的弱吸引力和水分子之间的强烈相互作用允许异常快速的水流，比宏观流体力学的预期高出几个数量级。一维水线上的质子迁移率也大大超过了整体。蛋白质似乎在生物功能中利用了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)。水在非极性约束下的不同寻常的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。有氧生命是基于一种利用氧气作为终端电子接收器的分子机械。膜结合的细胞色素c氧化酶(CcO)在线粒体和许多细菌中催化氧还原为水。在这个过程中释放出的能量 反应是保守的，通过将质子泵过线粒体或细菌膜，创建电化学质子梯度，驱动ATP的产生。在Kaila博士和Wikstrom博士(芬兰赫尔辛基大学)的合作下，我们通过分子动力学模拟探索了在这个过程中如何防止由CcO泵浦的质子倒流。我们发现，在CcO活性中心附近的保守谷氨酸242经历了质子化状态依赖的构象变化，这为泵浦机制提供了阀门。该阀门确保在任何时间点，质子通过膜的路径是有效不连续的，从而防止热力学上有利的质子回漏，同时保持质子转移的整体高效。压制 在生理条件下，质子泄漏的影响在线粒体中尤其重要，在这种情况下，ATP的产生是在高电化学质子梯度存在的情况下发生的。 纳米通道中的分子传输：细胞提供了一个高度拥挤的环境。这种拥挤强烈地影响了生物分子的扩散动力学。然而，我们仍然缺乏在拥挤环境中扩散的理论。与Mittal博士(NIDDK，NIH)和TRUSKETT博士(德克萨斯大学奥斯汀分校)合作，我们研究了流体在平行光滑硬壁之间的扩散动力学。我们发现垂直于壁面的位置相关扩散系数与局部堆积密度之间存在着意想不到的关联。我们可以用以下事实来解释这种正相关性：对于以排斥为主的流体，高密度区也具有最大的可用体积，这与观察到的快速局部扩散系数一致。重要的是，我们证实了扩散系数强烈偏离了整体流体行为，这使得在研究拥挤环境中的扩散时有必要进行修正，如细胞及其细胞器的扩散。

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.