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, 132 (34), 12091-7

Water in Cavity-Ligand Recognition

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Water in Cavity-Ligand Recognition

Riccardo Baron et al. J Am Chem Soc.

Abstract

We use explicit solvent molecular dynamics simulations to estimate free energy, enthalpy, and entropy changes along the cavity-ligand association coordinate for a set of seven model systems with varying physicochemical properties. Owing to the simplicity of the considered systems we can directly investigate the role of water thermodynamics in molecular recognition. A broad range of thermodynamic signatures is found in which water (rather than cavity or ligand) enthalpic or entropic contributions appear to drive cavity-ligand binding or rejection. The unprecedented, nanoscale picture of hydration thermodynamics can help the interpretation and design of protein-ligand binding experiments. Our study opens appealing perspectives to tackle the challenge of solvent entropy estimation in complex systems and for improving molecular simulation models.

Figures

Figure 1
Figure 1
Snapshot and schematic representation of the explicitly solvated hemispherical cavities and spherical ligands used in this study. The seven systems only differ for the charges on cavity, QC, and ligand, QL. Note that (ξ = 0) corresponds to wall surface.
Figure 2
Figure 2
Thermodynamic signature profile and water density maps along the binding coordinate ξ for a nonpolar ligand binding a nonpolar cavity (N,N). Left, top panel: Gibbs free energy, G (red), enthalpy, H (blue), and entropic term, −TS (green) are shown with their uncertainties (vertical bars). Left, bottom panel: water contribution to relative Gibbs free energy, GW (orange) and decomposed energies for ligand-water, ULW (green), cavity-water, UCW (black), and water−water, UWW (cyan) interactions. Water density (ρ*) distribution maps are shown for key snapshots along ξ using a color coding normalized with respect to bulk water, for which ρ* = 1. See Movie S1 for the corresponding dynamic hydration video.
Figure 3
Figure 3
Thermodynamic signature profiles and water density distribution maps along the (+,N) or (−,N) cavity−ligand binding coordinates. See Figure 2 legend for color coding as well as Movies S2 and S3 for dynamic hydration.
Figure 4
Figure 4
Thermodynamic signature profiles and water density distribution maps along the (−,+) or (+,−) cavity−ligand binding coordinates. See Figure 2 legend for color coding. In addition, the left, bottom panels report as well the change of cavity−ligand interaction energy, UCL (dotted black). See Movies S4 and S5 for dynamic hydration.
Figure 5
Figure 5
Thermodynamic signature profiles and water density distribution maps for ligand rejection along the (N,+) or (N,−) cavity−ligand coordinates. See Figure 2 legend for color coding as well as Movies S6 and S7 for dynamic hydration.
Figure 6
Figure 6
Two-state thermodynamic signatures of cavity−ligand recognition. Water is clearly an active player in six out of seven cases in which ligand binding/rejection is driven either by enthalpy (blue label) or by entropy (green label). See Table 1 for corresponding values.

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