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. 2018 Feb 13;14(2):512-526.
doi: 10.1021/acs.jctc.7b01076. Epub 2018 Jan 12.

The Role of Interfacial Water in Protein-Ligand Binding: Insights from the Indirect Solvent Mediated Potential of Mean Force

Di Cui  1 , Bin W Zhang  1 , Nobuyuki Matubayasi  2   3 , Ronald M Levy  1
Affiliations

The Role of Interfacial Water in Protein-Ligand Binding: Insights from the Indirect Solvent Mediated Potential of Mean Force

Di Cui et al. J Chem Theory Comput. .

Abstract

Classical density functional theory (DFT) can be used to relate the thermodynamic properties of solutions to the indirect solvent mediated part of the solute-solvent potential of mean force (PMF). Standard, but powerful numerical methods can be used to estimate the solute-solvent PMF from which the indirect part can be extracted. In this work we show how knowledge of the direct and indirect parts of the solute-solvent PMF for water at the interface of a protein receptor can be used to gain insights about how to design tighter binding ligands. As we show, the indirect part of the solute-solvent PMF is equal to the sum of the 1-body (energy + entropy) terms in the inhomogeneous solvation theory (IST) expansion of the solvation free energy. To illustrate the effect of displacing interfacial water molecules with particular direct/indirect PMF signatures on the binding of ligands, we carry out simulations of protein binding with several pairs of congeneric ligands. We show that interfacial water locations that contribute favorably or unfavorably at the 1-body level (energy + entropy) to the solvation free energy of the solute can be targeted as part of the ligand design process. Water locations where the indirect PMF is larger in magnitude provide better targets for displacement when adding a functional group to a ligand core.

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Figures

Figure 1
Figure 1
Representative structure of protein FXa with ligand XLC bound. For the ligand molecule, H1 and H2 in the label are the two hydrogen atoms which are modified to fluorine atoms.
Figure 2
Figure 2
(A) Transforming the ligand XLC to XLC-F1 causes the displacement of one water molecule in region 1 (B) Transforming XLC to XLC-F2 causes the displacement of one water molecule in region 2 (C) Chemical structures from XLC to XLC-F1 (D) Chemical structures from XLC to XLC-F2
Figure 3
Figure 3
(A) Transforming the ligand XLC to XLD causes the displacement of one water molecule in region 3 (B) Transforming XLC to XLD causes the displacement of three water molecules in region 4 (C) Chemical structures from XLC to XLD (D) Chemical structure of XLD-P1 (E) Chemical structure of XLD-P2
Figure 4
Figure 4
(A) Transforming the ligand IIA to IIB causes the displacement of one water molecule in region 5 (B) Transforming IIA to IIB causes the displacement of one water molecule in region 6 (C) Chemical structures from IIA to IIB (D) Chemical structure of IIB-P1 (E) Chemical structure of IIB-P2
Figure 5
Figure 5
(A) Transforming the ligand RRP to RTR causes the displacement of one water molecule in region 7 (B) The back transformation of RTR to RRP causes the displacement of one water molecule in region 8 (C) Chemical structures from RRP to RTR (D) Chemical structures from RTR to RRP
Figure 6
Figure 6
(A) Transforming the ligand biotin-O to biotin causes the displacement of one water molecule in region 9 (B) Transforming biotin-deuri to biotin causes the displacement of two water molecules in region 10 (C) Chemical structures from biotin-O to biotin (D) Chemical structures from biotin-deuri to biotin
Figure 7
Figure 7
(A) Transforming the ligand OC9 to F09 causes the displacement of one water molecule in region 11 (B) Chemical structures from OC9 to F09
Figure 8
Figure 8
ΔΔGpredict based on Equation 9 versus ΔΔGDDM using double decoupling method from 12 congeneric ligand pairs.
Scheme 1
Scheme 1
Thermodynamic cycle for ΔΔGbind by DFT analysis of displaced water (A) S change to L in vacuum and water (B) PS change to PL in vacuum and water
Scheme 2
Scheme 2
Thermodynamic cycle for ΔΔGbind by FEP
See this image and copyright information in PMC

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