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Towards full Quantum‐Mechanics‐based Protein–Ligand Binding Affinities
Author(s) -
Ehrlich Stephan,
Göller Andreas H.,
Grimme Stefan
Publication year - 2017
Publication title -
chemphyschem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.016
H-Index - 140
eISSN - 1439-7641
pISSN - 1439-4235
DOI - 10.1002/cphc.201700082
Subject(s) - solvation , affinities , chemistry , ligand (biochemistry) , implicit solvation , computational chemistry , protein ligand , qm/mm , quantum , molecular dynamics , crystallography , stereochemistry , physics , molecule , quantum mechanics , biochemistry , receptor , organic chemistry
Computational methods play a key role in modern drug design in the pharmaceutical industry but are mostly based on force fields, which are limited in accuracy when describing non‐classical binding effects, proton transfer, or metal coordination. Here, we propose a general fully quantum mechanical (QM) scheme for the computation of protein–ligand affinities. It works on a single protein cutout (of about 1000 atoms) and evaluates all contributions (interaction energy, solvation, thermostatistical) to absolute binding free energy on the highest feasible QM level. The methodology is tested on two different protein targets: activated serine protease factor X (FXa) and tyrosine‐protein kinase 2 (TYK2). We demonstrate that the geometry of the model systems can be efficiently energy‐minimized by using general purpose graphics processing units, resulting in structures that are close to the co‐crystallized protein–ligand structures. Our best calculations at a hybrid DFT level (PBEh‐3c composite method) for the FXa ligand set result in an overall mean absolute deviation as low as 2.1 kcal mol −1 . Though very encouraging, an analysis of outliers indicates that the structure optimization level, conformational sampling, and solvation treatment require further improvement.