title: Towards full Quantum-Mechanics-based Protein-Ligand Binding Affinities.
abstract: 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.
authors.affiliation: Mulliken Center for Theoretical Chemistry, Institut für Physikalische und Theoretische Chemie der Universität Bonn, Beringstr. 4, 53115, Bonn, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehrlich
authors.affiliation: Bayer Pharma AG, Drug Discovery-Chemical Research, Wuppertal, Germany.
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Göller
authors.affiliation: Mulliken Center for Theoretical Chemistry, Institut für Physikalische und Theoretische Chemie der Universität Bonn, Beringstr. 4, 53115, Bonn, Germany.
authors.forename: Stefan
authors.identifier: http://orcid.org/0000-0002-5844-4371
authors.initials: S
authors.lastname: Grimme
mesh_terms: D001665:Binding Sites; D005170:Factor X / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D011789:Quantum Theory; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D053634:TYK2 Kinase / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008024:Ligands; D005170:Factor X; D053634:TYK2 Kinase; C070139:TYK2 protein, human; D012697:Serine Endopeptidases
keywords: ab initio calculations; density functional calculations; drug design; noncovalent interactions; proteins