Water is an essential participant in the stability, structure, dynamics, and function of proteins and other biomolecules. Thermodynamically, changes in the aqueous environment affect the stability of biomolecules. Structurally, water participates chemically in the catalytic function of proteins and nucleic acids and physically in the collapse of the protein chain during folding through hydrophobic collapse and mediates binding through the hydrogen bond in complex formation. Water is a partner that slaves the dynamics of proteins, and water interaction with proteins affect their dynamics. Here we provide a review of the experimental and computational advances over the past decade in understanding the role of water in the dynamics, structure, and function of proteins. We focus on the combination of X-ray and neutron crystallography, NMR, terahertz spectroscopy, mass spectroscopy, thermodynamics, and computer simulations to reveal how water assist proteins in their function. The recent advances in computer simulations and the enhanced sensitivity of experimental tools promise major advances in the understanding of protein dynamics, and water surely will be a protagonist.

Understanding the structure and dynamics of water's constituent ions, proton and hydroxide, has been a subject of numerous experimental and theoretical studies over the last century. Besides their obvious importance in acid-base chemistry, these ions play an important role in numerous applications ranging from enzyme catalysis to environmental chemistry. Despite a long history of research, many fundamental issues regarding their properties continue to be an active area of research. Here, we provide a review of the experimental and theoretical advances made in the last several decades in understanding the structure, dynamics, and transport of the proton and hydroxide ions in different aqueous environments, ranging from water clusters to the bulk liquid and its interfaces with hydrophobic surfaces. The propensity of these ions to accumulate at hydrophobic surfaces has been a subject of intense debate, and we highlight the open issues and challenges in this area. Biological applications reviewed include proton transport along the hydration layer of various membranes and through channel proteins, problems that are at the core of cellular bioenergetics.

The diffusion of protons through water is understood within the framework of the Grotthuss mechanism, which requires that they undergo structural diffusion in a stepwise manner throughout the water network. Despite long study, this picture oversimplifies and neglects the complexity of the supramolecular structure of water. We use first-principles simulations and demonstrate that the currently accepted picture of proton diffusion is in need of revision. We show that proton and hydroxide diffusion occurs through periods of intense activity involving concerted proton hopping followed by periods of rest. The picture that emerges is that proton transfer is a multiscale and multidynamical process involving a broader distribution of pathways and timescales than currently assumed. To rationalize these phenomena, we look at the 3D water network as a distribution of closed directed rings, which reveals the presence of medium-range directional correlations in the liquid. One of the natural consequences of this feature is that both the hydronium and hydroxide ion are decorated with proton wires. These wires serve as conduits for long proton jumps over several hydrogen bonds.T he mechanism by which protons move through water is at the heart of acid-base chemistry reactions. Understanding the reaction coordinates of this process has been one of the most challenging problems in physical chemistry due to the sheer complexity of water's hydrogen bond network (1-4). Developing a molecular basis for these phenomena is of great relevance in energy conversion applications such as in the design of efficient fuel cells (5). Over 200 y ago, von Grotthuss proposed a mechanism by which water would undergo electrolytic decomposition (6). He imagined that proton conduction involved the collective shuttling of hydrogen atoms along water wires. The early 20th century found many of the great scientists of the time developing conceptual models to understand the properties of water and its constituent ions (7,8). Detailed insights into the mechanisms of proton transfer (PT) came much later from a combination of both ab initio molecular dynamics (AIMD) simulations (3, 9-13) and force-field approaches based on the empirical valence bond formalism (14-16). The current textbook picture of the Grotthuss mechanism that has resulted from these studies involves a stepwise hopping of the proton from one water molecule to the next (1,17,18). This process occurs on a timescale of 1-2 ps. For a successful transfer, the model requires solvent reorganization around the proton-receiving species to develop a coordination pattern like that of the species it will convert to, a process known as presolvation. In all of these characterizations of the Grotthuss mechanism, the role of the connectivity of the water network was not brought to the forefront (3, 19).Sometimes PT has also been thought to take on coherent character involving jumps of several protons simultaneously. In this spirit, Eigen (20) suggested that the proton could delocalize over extended hydrogen...

We report experimental and theoretical studies on water and protein dynamics following photoexcitation of apomyoglobin. Using site-directed mutation and with femtosecond resolution, we experimentally observed relaxation dynamics with a biphasic distribution of time scales, 5 and 87 ps, around the site Trp7. Theoretical studies using both linear response and direct nonequilibrium molecular dynamics (MD) calculations reproduced the biphasic behavior. Further constrained MD simulations with either frozen protein or frozen water revealed the molecular mechanism of slow hydration processes and elucidated the role of protein fluctuations. Observation of slow water dynamics in MD simulations requires protein flexibility, regardless of whether the slow Stokes shift component results from the water or protein contribution. The initial dynamics in a few picoseconds represents fast local motions such as reorientations and translations of hydrating water molecules, followed by slow relaxation involving strongly coupled water-protein motions. We observed a transition from one isomeric protein configuration to another after 10 ns during our 30 ns ground-state simulation. For one isomer, the surface hydration energy dominates the slow component of the total relaxation energy. For the other isomer, the slow component is dominated by protein interactions with the chromophore. In both cases, coupled water-protein motion is shown to be necessary for observation of the slow dynamics. Such biologically important water-protein motions occur on tens of picoseconds. One significant discrepancy exists between theory and experiment, the large inertial relaxation predicted by simulations but clearly absent in experiment. Further improvements required in the theoretical model are discussed.

Protein structures which form fibrils have recently been shown to absorb light at energies in the near UV range and to exhibit a structure-specific fluorescence in the visible range even in the absence of aromatic amino acids. However, the molecular origin of this phenomenon has so far remained elusive. Here, we combine ab initio molecular dynamics simulations and fluorescence spectroscopy to demonstrate that these intrinsically fluorescent protein fibrils are permissive to proton transfer across hydrogen bonds which can lower electron excitation energies and thereby decrease the likelihood of energy dissipation associated with conventional hydrogen bonds. The importance of proton transfer on the intrinsic fluorescence observed in protein fibrils is signified by large reductions in the fluorescence intensity upon either fully protonating, or deprotonating, the fibrils at pH = 0 or 14, respectively. Thus, our results point to the existence of a structure-specific fluorophore that does not require the presence of aromatic residues or multiple bond conjugation that characterize conventional fluorescent systems. The phenomenon may have a wide range of implications in biological systems and in the design of self-assembled functional materials.