title: Fully ab initio 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).
authors.affiliation: Universität Münster, Organisch-Chemisches Institut, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Antony
authors.forename: Stefan
authors.initials: S
authors.lastname: Grimme
mesh_terms: D008024:Ligands; D008958:Models, Molecular; D011506:Proteins / Q000737:chemistry*; D011789:Quantum Theory
chemical_list: D008024:Ligands; D011506:Proteins