Fully <i>ab initio</i> protein‐ligand interaction energies with dispersion corrected density functional theory

Abstract

Dispersion corrected density functional theory (DFT-D3) is used for fully ab initio protein-ligand (PL) interaction energy calculation via molecular fractionation with conjugated caps (MFCC) and applied to PL complexes from the PDB comprising 3680, 1798, and 1060 atoms. Molecular fragments with n amino acids instead of one in the original MFCC approach are considered, thereby allowing for estimating the three-body and higher many-body terms. n > 1 is recommended both in terms of accuracy and efficiency of MFCC. For neutral protein side-chains, the computed PL interaction energy is visibly independent of the fragment length n. The MFCC fractionation error is determined by comparison to a full-system calculation for the 1060 atoms containing PL complex. For charged amino acid side-chains, the variation of the MFCC result with n is increased. For these systems, using a continuum solvation model with a dielectricity constant typical for protein environments (ϵ = 4) reduces both the variation with n and improves the stability of the DFT calculations considerably. The PL interaction energies for two typical complexes obtained ab initio for the first time are found to be rather large (-30 and -54 kcal/mol).