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Cui D , Zhang BW , Matubayasi N , Levy RM
The Role of Interfacial Water in Protein-Ligand Binding: Insights from the Indirect Solvent Mediated Potential of Mean Force
J Chem Theory Comput. 2018 Feb 13;14(2) :512-526
PMID: 29262255    PMCID: PMC5897112   
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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.
1549-9626 Cui, Di Zhang, Bin W ORCID: http://orcid.org/0000-0003-3007-4900 Matubayasi, Nobuyuki ORCID: http://orcid.org/0000-0001-7176-441X Levy, Ronald M ORCID: http://orcid.org/0000-0001-8696-5177 R01 GM030580/GM/NIGMS NIH HHS/United States S10 OD020095/OD/NIH HHS/United States Journal Article United States J Chem Theory Comput. 2018 Feb 13;14(2):512-526. doi: 10.1021/acs.jctc.7b01076. Epub 2018 Jan 12.