Abstract
Proteins interact with their aqueous surroundings, thereby modifying the physical properties of the solvent. The extent of this perturbation has been investigated by numerous methods in the past half-century, but a consensus has still not emerged regarding the spatial range of the perturbation. To a large extent, the disparate views found in the current literature can be traced to the lack of a rigorous definition of the perturbation range. Stating that a particular solvent property differs from its bulk value at a certain distance from the protein is not particularly helpful since such findings depend on the sensitivity and precision of the technique used to probe the system. What is needed is a well-defined decay length, an intrinsic property of the protein in a dilute aqueous solution, that specifies the length scale on which a given physical property approaches its bulk-water value. Based on molecular dynamics simulations of four small globular proteins, we present such an analysis of the structural and dynamic properties of the hydrogen-bonded solvent network. The results demonstrate unequivocally that the solvent perturbation is short-ranged, with all investigated properties having exponential decay lengths of less than one hydration shell. The short range of the perturbation is a consequence of the high energy density of bulk water, rendering this solvent highly resistant to structural perturbations. The electric field from the protein, which under certain conditions can be long-ranged, induces a weak alignment of water dipoles, which, however, is merely the linear dielectric response of bulk water and, therefore, should not be thought of as a structural perturbation. By decomposing the first hydration shell into polarity-based subsets, we find that the hydration structure of the nonpolar parts of the protein surface is similar to that of small nonpolar solutes. For all four examined proteins, the mean number of water-water hydrogen bonds in the nonpolar subset is within 1% of the value in bulk water, suggesting that the fragmentation and topography of the nonpolar protein-water interface has evolved to minimize the propensity for protein aggregation by reducing the unfavorable free energy of hydrophobic hydration.
Highlights
In their comprehensive review of protein hydration,1 Irwin Kuntz and Walter Kauzmann concluded: “Second and third layers of water would be expected to show properties sufficiently similar to bulk water that it is not clear that any of the techniques we have discussed will detect these water molecules as distinct from bulk water.” Yet, in the ensuing 44 years, numerous claims of “long-range” protein-induced perturbations of water structure and dynamics have appeared in the literature
For all four examined proteins, the mean number of water-water hydrogen bonds in the nonpolar subset is within 1% of the value in bulk water, suggesting that the fragmentation and topography of the nonpolar protein-water interface has evolved to minimize the propensity for protein aggregation by
Smolin and Winter19 found that the mean water-water hydrogen bond (HB) number in the first hydration shell of staphylococcal nuclease is 17.6% lower than in bulk water, whereas we find a smaller reduction of 12.7% ± 0.6%. (Note that these figures exclude water-protein HBs.) For the nonpolar subset, they found a reduction of the mean HB number by 7.1%, while we find 1.0% ± 0.1%
Summary
In their comprehensive review of protein hydration, Irwin Kuntz and Walter Kauzmann concluded: “Second and third layers of water would be expected to show properties sufficiently similar to bulk water that it is not clear that any of the techniques we have discussed will detect these water molecules as distinct from bulk water.” Yet, in the ensuing 44 years, numerous claims of “long-range” protein-induced perturbations of water structure and dynamics have appeared in the literature. In their comprehensive review of protein hydration, Irwin Kuntz and Walter Kauzmann concluded: “Second and third layers of water would be expected to show properties sufficiently similar to bulk water that it is not clear that any of the techniques we have discussed will detect these water molecules as distinct from bulk water.”. In the ensuing 44 years, numerous claims of “long-range” protein-induced perturbations of water structure and dynamics have appeared in the literature. Spectroscopic data have been interpreted in terms of perturbed water dynamics extending several nanometers from the protein surface.. Theoretical and computational studies have suggested ferroelectric water ordering, modified water structure, and vibrational signal transduction over nanometer distances from the protein surface. The main objective of the present work is to determine the range of the protein-induced perturbation of the solvent Macroscopic observations have been taken as evidence for micrometer-ranged alterations of water structure, including phase transitions. Spectroscopic data have been interpreted in terms of perturbed water dynamics extending several nanometers from the protein surface. Theoretical and computational studies have suggested ferroelectric water ordering, modified water structure, and vibrational signal transduction over nanometer distances from the protein surface.
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