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Review
. 2016 Jul 13;116(13):7673-97.
doi: 10.1021/acs.chemrev.5b00664. Epub 2016 May 17.

Water Determines the Structure and Dynamics of Proteins

Marie-Claire Bellissent-Funel  1 , Ali Hassanali  2 , Martina Havenith  3 , Richard Henchman  4 , Peter Pohl  5 , Fabio Sterpone  6 , David van der Spoel  7 , Yao Xu  3 , Angel E Garcia  8
Affiliations
Review

Water Determines the Structure and Dynamics of Proteins

Marie-Claire Bellissent-Funel et al. Chem Rev. .

Abstract

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
(a) Molecular jump mechanism. (b) Schematic figure with a protein interface and the three types of sites, respectively hydrophobic, H-bond donor, and H-bond acceptor, together with a pictorial representation of the types of perturbation they induce on water dynamics (excluded volume and H-bond strength factors). This figure is reproduced with permission from ref . Copyright 2013 Royal Society of Chemistry.
Figure 2
Figure 2
Fluctuations in the interloop region during 1 ms. (A) Volume of the convex hull spanning the four internal hydration sites. (B) Backbone RMSD, relative to crystal structure 5pti, for the residues defining the hull. (C) Number of water molecules inside the hull. (D) Dihedral angle χ1(C14), with disulfide isomeric states color-coded: M1 (blue), M2 (magenta), M3 (yellow), mC14 (red), mC38 (green), and other (gray). The time series values plotted here are either averaged over consecutive 25 ns windows (A–C) or sampled with 25 ns resolution (D). The full-trajectory distributions are projected on the right-hand axis. This figure is reprinted from ref . Copyright 2013 American Chemical Society.
Figure 3
Figure 3
Mean square displacements in dry and wet myoglobin. The sharp increase in mean square displacements at around 200 K for the hydrated sample is absent in the dehydrated sample. Reproduced with permission from ref . Copyright 1989 Macmillan Publishers Ltd., Nature.
Figure 4
Figure 4
Temperature dependence if the hydrogen atom mean-square displacement of lysozyme hydrated with a monolayer of D2O. Zanotti et al. observed a strong correlation between the local reorientational transition observed in water at 220 K, 2 rot water>, and the onset of the long time (1 ns) large amplitude overdamped motions responsible for the <u2 protein> to increase above 220 K. The correlation between protein dynamical crossovers at 150 and 220 K and interfacial water rotational dynamics (no correlation with translational dynamics): it was suggested that the sole hydration water rotational dynamics trigger the protein dynamics. This figure is reproduced with permission from ref . Copyright 2007 Springer.
Figure 5
Figure 5
A schematic view of the kinetic absorption spectroscopy setup.
Figure 6
Figure 6
Pair correlation function d(r) for a dry deuterated C-phycocyanin(d-CPC) protein at 295 K and for a D2O-hydrated (h = 0.365) d-CPC protein at different temperatures. This figure is reproduced with permission from ref . Copyright 1993 Elsevier.
Figure 7
Figure 7
Structures resulting from three replicate simulations of the C-terminal fragment of L7/L12 ribosomal protein showing that solvation (blue, transparent) of the protein is quite reproducible. Figure adapted with permission from ref . Copyright 2009 Royal Society of Chemistry.
Figure 8
Figure 8
Calculated P–T stability diagram for the Trp-cage miniprotein shows an elliptical shape that predicts pressure and cold denaturation at high pressures. The ΔG = 0 curve is the innermost contour. Other contours show ΔG = −15, −10, and 15 kJ mol-1. The dotted lines show the thermodynamic states sampled in two independent REMD simulations. The black line shows the ΔV = 0 isochore; the solid red line shows the ΔS = 0 isentrope. This figure is reproduced with permission from ref . Copyright 2010 Wiley-Liss, Inc.
Figure 9
Figure 9
Calculated P–T diagram for a small protein and peptides. The colored lines are the loci of the 0.5 fraction folded for the Trp-cage (magenta), 0.5 fraction folded for the GB1 β-hairpin (blue), and 0.25 fraction folded for the AK16 (green) α helix. Dashed lines are in the vicinity of the simulation data. The back line is a numerical estimate of the spinoidal of the bulk solution. The figure and caption are reprinted from ref . Copyright 2014 American Chemical Society.
Figure 10
Figure 10
(A) Guinier representation [ln I = f(Q2)] of SANS spectra of apo-calmodulin at 5 g/L for several temperatures, between 20 °C (in blue) and 85 °C (in red). Straight full lines are fits using Guinier laws leading to radius of gyration. The red curved full line is a fit of SANS spectra of apo-calmodulin at 85 °C, using the Debye law. (B) Radius of gyration, R g, of apo-calmodulin in D2O at 5 g/L as a function of temperature. In black is the fit with a three-state transition model, with the same thermodynamic parameters as for circular dichroism. (C) Adapted Kratky [Q2.3.I(Q) = f(Q)] representation of SANS spectra at 18 g/L of apo-calmodulin at several temperatures between 20 °C (in blue) and 77 °C (in red). (D) Adapted Kratky [Q2.3. I(Q) = f(Q)] representation of SANS spectra at 5 g/L of apo calmodulin at 20 °C (in blue) and 85 °C (in red). The samples are solutions of apo-calmodulin in a 50 mM D2O Tris buffer, pD = 7.6 with 80 mM KCl and 500 μM EDTA. The figure and caption are reproduced with permission from ref . Copyright 2012 Elsevier B.V.
Figure 11
Figure 11
(Top) Translational density of states of (a) bulk and (b) lysozyme hydration water determined by MD simulations at 0.1 MPa (1 atm) and 600 MPa. (Middle) Rotational density of states of (c) bulk and (d) lysozyme hydration water determined by MD simulations at 0.1 and 600 MPa. The curves have been determined by averaging the g(x) of bulk and hydration water over 10 and 25 10 ps trajectories, respectively. The translational g(x) of bulk and hydration water have been fitted using a log-normal and Gaussian function that represents the O_O_O bending and O_O stretching bands, respectively, denoted as I and II. The two bands determined for the g(x) of bulk and hydration water at 1 atm are shown as dashed gray lines in (a) and (b), respectively. The pressure dependence of the positions of these bands is shown in (e). This figure is reproduced with permission from ref . Copyright 2013 Wiley Periodicals, Inc.
Figure 12
Figure 12
Macroscopic hydrodynamics (Hagen–Poiseuille’s flow) versus single-file flow (not drawn to scale). The water molecules in contact with the walls of a macroscopic tube are thought to be immobile (nonslip condition), whereas the water molecules within nanoscopic channels may be as mobile as in bulk water.
Figure 13
Figure 13
Total number N H of hydrogen bonds that single-file water molecules may form with pore-lining residues while traversing the channel governs water mobility. The latter is expressed in terms of the water diffusion coefficient D w in the pore. The data for the peptidic channels gramicidin, midigramicidin, and minigramicidin are from refs and for the potassium channel KcsA from Hoomann et al., 2013 (with corrections as outlined in ref 287), for the aquaporins AQP1, AQPZ, and GlpF from ref and for nanotubes from ref . The figure is reproduced with permission from ref . Copyright 2015 American Association for the Advancement of Science.
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