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.
| Rosta, Edina; Buchete, Nicolae-Viorel; Hummer, Gerhard (2009) Thermostat artifacts in replica exchange molecular dynamics simulations. J Chem Theory Comput 5:1393-1399 |
| Kim, Young C; Wikstrom, Marten; Hummer, Gerhard (2009) Kinetic gating of the proton pump in cytochrome c oxidase. Proc Natl Acad Sci U S A 106:13707-12 |
| Kofinger, Jurgen; Hummer, Gerhard; Dellago, Christoph (2009) A one-dimensional dipole lattice model for water in narrow nanopores. J Chem Phys 130:154110 |
| Kaila, Ville R I; Verkhovsky, Michael I; Hummer, Gerhard et al. (2009) Mechanism and energetics by which glutamic acid 242 prevents leaks in cytochrome c oxidase. Biochim Biophys Acta 1787:1205-14 |
| Kofinger, Jurgen; Hummer, Gerhard; Dellago, Christoph (2008) Macroscopically ordered water in nanopores. Proc Natl Acad Sci U S A 105:13218-22 |
| Mittal, Jeetain; Truskett, Thomas M; Errington, Jeffrey R et al. (2008) Layering and position-dependent diffusive dynamics of confined fluids. Phys Rev Lett 100:145901 |
| Rasaiah, Jayendran C; Garde, Shekhar; Hummer, Gerhard (2008) Water in nonpolar confinement: from nanotubes to proteins and beyond. Annu Rev Phys Chem 59:713-40 |
| Kaila, Ville R I; Verkhovsky, Michael; Hummer, Gerhard et al. (2008) Prevention of leak in the proton pump of cytochrome c oxidase. Biochim Biophys Acta 1777:890-2 |
| Kaila, Ville R I; Verkhovsky, Michael I; Hummer, Gerhard et al. (2008) Glutamic acid 242 is a valve in the proton pump of cytochrome c oxidase. Proc Natl Acad Sci U S A 105:6255-9 |
| Hummer, Gerhard (2007) Water pulls the strings in hydrophobic polymer collapse. Proc Natl Acad Sci U S A 104:14883-4 |
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