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。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。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. 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. We have made a number of advances in areas where water, protons, and ions are connected to protein function. 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 the production of ATP. In collaboration with Dr. Wikstrom (University of Helsinki, Finland) and Dr. Kim (Naval Research Lab, Washington, DC), we use molecular simulations and detailed kinetic models of the redox-coupled proton pump in CcO. In 2009/2010, we could show how time-dependent external electric fields can be used to probe the function of this molecular machine (Kim et al, Phys. Rev. Lett. 2009). We showed that the proton pumping efficiency and the electronic currents in steady state depend sensitively on the frequency and amplitude of the applied field, allowing us to distinguish between different microscopic mechanisms of the machine. From a spectral analysis we could identify dominant reaction steps that were consistent with an electron-gated proton pumping mechanism of CcO. This study provides insights into the mechanism of CcO function, and opens the way for novel experimental characterizations. Ion channel gating. We have studied the gating transition of pentameric ligand-gated ion channels (Zhu, Hummer, Biophys. J., 2009). These channels form an important family of membrane proteins that play key roles in many physiological processes, including nerve signaling. A key element of their function is the controlled opening and closing of a pore to gate the ionic current across the membrane. Based on recent crystal structures of two prokaryotic members of the family in open and closed states, we constructed mixed elastic network models to study the motions of the transmembrane domain during channel opening and closing. To explore the conformational changes in the gating transition, a coarse-grained transition path is computed that smoothly connects the closed and open conformations of the channel. We find that the conformational transition involves no major rotations of the transmembrane helices, and is instead characterized by a concerted iris-like tilting of helices M2 and M3. In addition, helix M2 changes its bending state, which results in an early closure of the pore during the open-to-closed transition.