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. 2019 Jul 10;14(7):e0219473.
doi: 10.1371/journal.pone.0219473. eCollection 2019.

A molecular reconstruction approach to site-based 3D-RISM and comparison to GIST hydration thermodynamic maps in an enzyme active site

Crystal Nguyen  1 , Takeshi Yamazaki  2 , Andriy Kovalenko  3   4 , David A Case  5 , Michael K Gilson  1 , Tom Kurtzman  6 , Tyler Luchko  7
Affiliations

A molecular reconstruction approach to site-based 3D-RISM and comparison to GIST hydration thermodynamic maps in an enzyme active site

Crystal Nguyen et al. PLoS One. .

Abstract

Computed, high-resolution, spatial distributions of solvation energy and entropy can provide detailed information about the role of water in molecular recognition. While grid inhomogeneous solvation theory (GIST) provides rigorous, detailed thermodynamic information from explicit solvent molecular dynamics simulations, recent developments in the 3D reference interaction site model (3D-RISM) theory allow many of the same quantities to be calculated in a fraction of the time. However, 3D-RISM produces atomic-site, rather than molecular, density distributions, which are difficult to extract physical meaning from. To overcome this difficulty, we introduce a method to reconstruct molecular density distributions from atomic-site density distributions. Furthermore, we assess the quality of the resulting solvation thermodynamics density distributions by analyzing the binding site of coagulation Factor Xa with both GIST and 3D-RISM. We find good qualitative agreement between the methods for oxygen and hydrogen densities as well as direct solute-solvent energetic interactions. However, 3D-RISM predicts lower energetic and entropic penalties for moving water from the bulk to the binding site.

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Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: M.K.G. has an equity interest in and is a cofounder and scientific advisor of VeraChem LLC. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Cross section of the additively combined oxygen and hydrogen site solute-water energy density distributions about Factor Xa.
Calculation from (A) 3D-RISM-PSE-3-UCT, (C) 3D-RISM-PSE-3, and (B) the difference.
Fig 2
Fig 2. Solute-water pair distribution functions in the FXa binding site.
Oxygen pair distribution functions as calculated by (A) MD and (B) 3D-RISM. Hydrogen pair distribution functions as calculated by (C) MD and (D) 3D-RISM. Isosurfaces are shown for 4 (yellow) and 8 (blue) times bulk density. The FXa solvent accessible surface is shown in white. Numbers identify density regions that are discussed in the text.
Fig 3
Fig 3. Solute-water energy density distributions in the FXa binding site.
Energy density distribution were calculated using (A) 3D-RISM with additively combined oxygen and hydrogen site solute-water energy density distributions, (B) GIST, and (C) 3D-RISM with molecular reconstruction. Isosurfaces are shown for -2 (dark red), -1 (light red), 1 (light blue), and 2 (dark blue) kcal/mol/Å3. The FXa solvent accessible surface is shown in white. Numbers identify density regions that are discussed in the text.
Fig 4
Fig 4. Water-water energy density distributions in the FXa binding site.
(A) GIST and (B) 3D-RISM with molecular reconstruction. Coloring and numbering are as in Fig 3.
Fig 5
Fig 5. Total water energy density distributions in the FXa binding site.
(A) GIST and (B) 3D-RISM with molecular reconstruction. Coloring and numbering are as in Fig 3.
Fig 6
Fig 6. Total water entropy (-TΔS) density distributions in the FXa binding site.
(A) GIST and (B) 3D-RISM with molecular reconstruction. Isosurfaces are shown for -2 (dark red), -1 (light red), 1 (light blue), and 2 (dark blue) kcal/mol/Å3. The FXa solvent accessible surface is shown in white. Numbers identify regions that are discussed in the text.
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References

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