Pairwise Additivity and Three-Body Contributions for Density Functional Theory-Based Protein-Ligand Interaction...

Area of Science:

• Computational Chemistry
• Biophysics
• Drug Design

Background:

• Protein-ligand binding energy prediction is vital for computer-assisted drug design.
• Interaction energies are often approximated by summing pairwise residue-ligand contributions.
• The accuracy of this pairwise additivity approximation needs validation.

Purpose of the Study:

• To test the validity of the pairwise additivity approximation for protein-ligand interaction energies.
• To evaluate the significance of three-body contributions to interaction energy.
• To investigate the influence of density functional theory (DFT) methods on approximation accuracy.

Main Methods:

• Calculated protein-ligand binding energies for the sulfotransferase-l-DOPA complex.
• Employed 16 DFT methods with varying exact exchange.
• Assessed pairwise additivity and calculated three-body contributions.

Main Results:

• The degree of exact exchange in DFT methods directly impacts the accuracy of pairwise additivity.
• Three-body interaction energies were found to be significant for the studied system.
• The significance of three-body interactions can be accurately predicted.

Conclusions:

• Pairwise additivity is a useful approximation but its accuracy depends on the DFT method used.
• Three-body effects are important and should be considered for precise binding energy calculations.
• Predicting three-body contributions enhances the reliability of computational drug design models.