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.2019 May 28;59(5):2407-2422.
doi: 10.1021/acs.jcim.9b00009. Epub 2019 Mar 22.

Protein Solvent Shell Structure Provides Rapid Analysis of Hydration Dynamics

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Protein Solvent Shell Structure Provides Rapid Analysis of Hydration Dynamics

Jayangika N Dahanayake et al. J Chem Inf Model..

Abstract

The solvation layer surrounding a protein is clearly an intrinsic part of protein structure-dynamics-function, and our understanding of how the hydration dynamics influences protein function is emerging. We have recently reported simulations indicating a correlation between regional hydration dynamics and the structure of the solvation layer around different regions of the enzyme Candida antarctica lipase B, wherein the radial distribution function (RDF) was used to calculate the pairwise entropy, providing a link between dynamics (diffusion) and thermodynamics (excess entropy) known as Rosenfeld scaling. Regions with higher RDF values/peaks in the hydration layer (the first peak, within 6 Å of the protein surface) have faster diffusion in the hydration layer. The finding thus hinted at a handle for rapid evaluation of hydration dynamics at different regions on the protein surface in molecular dynamics simulations. Such an approach may move the analysis of hydration dynamics from a specialized venture to routine analysis, enabling an informatics approach to evaluate the role of hydration dynamics in biomolecular function. This paper first confirms that the correlation between regional diffusive dynamics and hydration layer structure (via water center of mass around protein side-chain atom RDF) is observed as a general relationship across a set of proteins. Second, it seeks to devise an approach for rapid analysis of hydration dynamics, determining the minimum amount of information and computational effort required to get a reliable value of hydration dynamics from structural data in MD simulations based on the protein-water RDF. A linear regression model using the integral of the hydration layer in the water-protein RDF was found to provide statistically equivalent apparent diffusion coefficients at the 95% confidence level for a set of 92 regions within five different proteins. In summary, RDF analysis of 10 ns of data after simulation convergence is sufficient to accurately map regions of fast and slow hydration dynamics around a protein surface. Additionally, it is anticipated that a quick look at protein-water RDFs, comparing peak heights, will be useful to provide a qualitative ranking of regions of faster and slower hydration dynamics at the protein surface for rapid analysis when investigating the role of solvent dynamics in protein function.

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Figures

Figure 1.
Figure 1.
Comparison of radial distribution functions [RDF, or g(r)] of water center of mass around protein side chain atoms (black line) and water oxygen (red line) calculated around one region (residues 1-12) of CALB protein.
Figure 2.
Figure 2.
External solvent-exposed regions of RNase A protein divided by secondary structure that were used for analysis of solvent shell structure and regional hydration dynamics: blue, residues 1–5; red, residues 12–22; cyan, residues 27–29; dark blue, residues 31–43; dark pink, residues 49–53; orange, residues 59–63; beige, residues 67–71; magenta, residues 76–78; green, residues 85–96; dark purple, residues 100–105; forest green, residues 113–115; yellow, residues 116–120; aquamarine, residues 122–124.
Figure 3.
Figure 3.
Radial distribution functions [RDF, or g(r)] of water center of mass around protein side chain atoms calculated around (a) α-helices in CALB protein (b) one region of RNase A protein (residues 73-75) with an anomalous hydration shell structure.
Figure 4.
Figure 4.
Mean square displacement graphs for the five proteins (red-CALB, blue-CheY, green-HEWL, magenta-RNase A, orange-SC) and bulk water (black), (a) for 200 ps and (b) for first 5 ps. Two regions (solid line and dotted line) for each protein are shown.
Figure5.
Figure5.
Diffusion maps for each (a) CALB protein and (b) HEWL protein. Protein regions are color coded according to diffusion coefficients (purple > 1.90 x 10−5 cm2/s, blue 1.80-1.89 x 10−5 cm2/s, green 1.70-1.79 x 10−5 cm2/s, yellow 1.60-1.69 x 10−5 cm2/s, orange 1.50-1.59 x 10−5 cm2/s, red < 1.50 x 10−5 cm2/s water diffusion coefficients).
Figure 6.
Figure 6.
A color-coded map for RNase A protein hydration layer dynamics and structure. (a) Protein hydration shell water diffusion coefficients mapped to RNase A structure (Green > 1.9 x 10−5 cm2/s, yellow 1.4-1.9 x 10−5 cm2/s, red < 1.4 x 10−5 cm2/s water diffusion coefficients). (b) Water center of mass RDF around RNase A protein regions. Shaded regions indicate hydration dynamics according to the regional protein hydration shell water diffusion coefficients (Green > 1.9 × 10−5 cm2/s, yellow 1.4–1.9 × 10–5 cm2/s, red < 1.4 × 10–5 cm2/s water diffusion coefficients). Color code for the RDF graphs corresponding to different regions is same as the color code used in Figure 1.
Figure 7.
Figure 7.
Linear correlation of local water structure/density obtained using integration of the RDF, with regional hydration layer diffusive dynamics across a set of five proteins, with error bars and a 95% confidence interval according tot-test values for the diffusion coefficients.
Figure 8.
Figure 8.
Plot of the residual error in the diffusion coefficients, as a function of the density obtained from RDF hydration layer integral (to r=6 Å) using the linear regression model. The red line shows a residual error of zero.
Figure 9.
Figure 9.
Linear correlation of local water structure/density obtained using integration of the RDF, with local hydration layer apparent diffusion coefficients for CALB and HEWL protein with TIP4P water model.
Figure 10.
Figure 10.
Linear correlation of local water structure/density obtained using integration of the RDF, with local solvent shell water diffusion coefficients for CALB and HEWL protein with OPLSAA force field.
Figure 11.
Figure 11.
Linear correlation of local water structure/density obtained using integration of the RDF of first 10 ns after reaching equilibrium, with local solvent shell water diffusion coefficients.
Figure 12.
Figure 12.
Linear correlation of local water structure/density obtained using integration of the RDF, with local solvent shell water diffusion coefficients at (a) 278 K and (b) 288 K
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