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Pairwise additivity and three-body contributions for Density Functional Theory-based protein-ligand interaction energies

Schulze, C. A. E. and Cafiero, M. ORCID: (2024) Pairwise additivity and three-body contributions for Density Functional Theory-based protein-ligand interaction energies. Journal of Physical Chemistry B, 128 (10). pp. 2326-2336. ISSN 1520-5207

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To link to this item DOI: 10.1021/acs.jpcb.3c07456


The prediction of protein-ligand binding energies is crucial in computer-assisted drug design. This property can be calculated in a straightforward fashion as the difference in the energies between a binding-site-ligand complex and the separated binding site and ligand. Often, though, there is value in knowing how different amino acid residues in the protein binding site will interact with the ligand. In this case, the interaction energy can be calculated as a sum of pairwise energies between each amino acid residue in the binding site and the ligand, and the sum of these energies is often equated with the total interaction energy. The validity of this pairwise additivity approximation can be assessed by experimental evidence such as double mutant cycles. In this work we test the pairwise additivity approximation on the sulfotransferase-L-DOPA complex for sixteen density functional theory (DFT) methods with varying degrees of exact (Hartree-Fock) exchange. Several “families” of functionals are studied, including BLYP, B3LYP and CAM-B3LYP, as well as M06L, M06 and M062X. We also calculate the three-body contributions to interaction energy for the same DFT methods and assess when they are significant. We find that the amount of exact exchange or other non-local contributions has a direct influence on how closely the sum of pairwise energies approximates the total interaction energy. We also find that three-body interactions can be significant, and that their significance can be predicted with good accuracy.

Item Type:Article
Divisions:Life Sciences > School of Chemistry, Food and Pharmacy > Department of Chemistry
ID Code:115260
Publisher:American Chemical Society


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