title: Pairwise decomposition of residue interaction energies using semiempirical quantum mechanical methods in studies of protein-ligand interaction.
abstract: Pairwise decomposition of the interaction energy between molecules is shown to be a powerful tool that can increase our understanding of macromolecular recognition processes. Herein we calculate the pairwise decomposition of the interaction energy between the protein human carbonic anhydrase II (HCAII) and the fluorine-substituted ligand N-(4-sulfamylbenzoyl)benzylamine (SBB) using semiempirical quantum mechanics based methods. We dissect the interaction between the ligand and the protein by dividing the ligand and the protein into subsystems to understand the structure-activity relationships as a result of fluorine substitution. In particular, the off-diagonal elements of the Fock matrix that is composed of the interaction between the ionic core and the valence electrons and the exchange energy between the subsystems or atoms of interest is examined in detail. Our analysis reveals that the fluorine-substituted benzylamine group of SBB does not directly affect the binding energy. Rather, we find that the strength of the interaction between Thr199 of HCAII and the sulfamylbenzoyl group of SBB affects the binding affinity between the protein and the ligand. These observations underline the importance of the sulfonamide group in binding affinity as shown by previous experiments (Maren, T. H.; Wiley: C. E. J. Med. Chem. 1968, 11, 228-232). Moreover, our calculations qualitatively agree with the structural aspects of these protein-ligand complexes as determined by X-ray crystallography.
authors.affiliation: Department of Chemistry, 104 Chemistry Building, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Raha
authors.forename: Arjan J
authors.initials: AJ
authors.lastname: van der Vaart
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Riley
authors.forename: Martin B
authors.initials: MB
authors.lastname: Peters
authors.forename: Lance M
authors.initials: LM
authors.lastname: Westerhoff
authors.forename: Hwanho
authors.initials: H
authors.lastname: Kim
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Merz
mesh_terms: D001596:Benzylamines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D007700:Kinetics; D011789:Quantum Theory; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013816:Thermodynamics
chemical_list: D001596:Benzylamines; D013449:Sulfonamides; D024402:Carbonic Anhydrase II