The electrostatic embedding contribution to DFT calculations of ligand-amino acid residues interaction.

In this work, we demonstrate that the inclusion of long-range interactions has a significant impact on the estimation of ligand-protein binding energies. Within the scope of the electrostatically embedded adaptation of the molecular fragmentation with conjugated caps (EE-AMFCC) scheme, we unveil the role played by long-range contributions in distinct levels of quantum mechanical calculations. As a prototypical system, we consider ibuprofen coupled to the human serum albumin. In particular, we show that some relevant ligand-residue interaction energies can only be accurately captured in density functional theory (DFT) approaches when the electrostatic background is properly represented by an explicit point charge distribution. Graphical Abstract (left) The binding site FA3/FA4 of HSA containing the attached IBU. (right) Absolute value of difference between the biding energies calculated including the electrostatic embedding and the energies calculated without the electrostatic embedding using the HF, B3LYP, CAM-B3LYP, and MP2 methodologies.