title: Histidine-Aromatic Interactions in Proteins and Protein-Ligand Complexes:  Quantum Chemical Study of X-ray and Model Structures.
abstract: His-aromatic complexes, with the His located above the aromatic plane, are stabilized by π-π, δ(+)-π and/or cation-π interactions according to whether the His is neutral or protonated and the partners are in stacked or T-shape conformations. Here we attempt to probe the relative strength of these interactions as a function of the geometry and protonation state, in gas phase, in water and protein-like environments (acetone, THF and CCl4), by means of quantum chemistry calculations performed up to second order of the Møller-Plesset pertubation theory. Two sets of conformations are considered for that purpose. The first set contains 89 interactions between His and Phe, Tyr, Trp, or Ade, observed in X-ray structures of proteins and protein-ligand complexes. The second set contains model structures obtained by moving an imidazolium/imidazole moiety above a benzene ring or an adenine moiety. We found that the protonated complexes are much more stable than the neutral ones in gas phase. This higher stability is due to the electrostatic contributions, the electron correlation contributions being equally important in the two forms. Thus, π-π and δ(+)-π interactions present essentially favorable electron correlation energy terms, whereas cation-π interactions feature in addition favorable electrostatic energies. The protonated complexes remain more stable than the neutral ones in protein-like environments, but the difference is drastically reduced. Furthermore, the T-shape conformation is undoubtedly more favorable than the stacked one in gas phase. This advantage decreases in the solvents, and the stacked conformation becomes even slightly more favorable in water. The frequent occurrence of His-aromatic interactions in catalytic sites, at protein-DNA or protein-ligand interfaces and in 3D domain swapping proteins emphasize their importance in biological processes.
authors.affiliation: Service de Chimie quantique et Photophysique, Université Libre de Bruxelles, CP 160/09, 50 Avenue F.D. Roosevelt, B-1050 Bruxelles, Belgium, Unité de Bioinformatique génomique et structurale, Université Libre de Bruxelles, CP 165/61, 50 Avenue F.D. Roosevelt, Institut de Pharmacie, B-1050 Bruxelles, Belgium, and Service de Chimie générale, Université Libre de Bruxelles, CP 206/04, Bld du Triomphe, B-1050 Bruxelles, Belgium.
authors.forename: Emilie
authors.initials: E
authors.lastname: Cauët
authors.affiliation: Service de Chimie quantique et Photophysique, Université Libre de Bruxelles, CP 160/09, 50 Avenue F.D. Roosevelt, B-1050 Bruxelles, Belgium, Unité de Bioinformatique génomique et structurale, Université Libre de Bruxelles, CP 165/61, 50 Avenue F.D. Roosevelt, Institut de Pharmacie, B-1050 Bruxelles, Belgium, and Service de Chimie générale, Université Libre de Bruxelles, CP 206/04, Bld du Triomphe, B-1050 Bruxelles, Belgium.
authors.forename: Marianne
authors.initials: M
authors.lastname: Rooman
authors.affiliation: Service de Chimie quantique et Photophysique, Université Libre de Bruxelles, CP 160/09, 50 Avenue F.D. Roosevelt, B-1050 Bruxelles, Belgium, Unité de Bioinformatique génomique et structurale, Université Libre de Bruxelles, CP 165/61, 50 Avenue F.D. Roosevelt, Institut de Pharmacie, B-1050 Bruxelles, Belgium, and Service de Chimie générale, Université Libre de Bruxelles, CP 206/04, Bld du Triomphe, B-1050 Bruxelles, Belgium.
authors.forename: René
authors.initials: R
authors.lastname: Wintjens
authors.affiliation: Service de Chimie quantique et Photophysique, Université Libre de Bruxelles, CP 160/09, 50 Avenue F.D. Roosevelt, B-1050 Bruxelles, Belgium, Unité de Bioinformatique génomique et structurale, Université Libre de Bruxelles, CP 165/61, 50 Avenue F.D. Roosevelt, Institut de Pharmacie, B-1050 Bruxelles, Belgium, and Service de Chimie générale, Université Libre de Bruxelles, CP 206/04, Bld du Triomphe, B-1050 Bruxelles, Belgium.
authors.forename: Jacques
authors.initials: J
authors.lastname: Liévin
authors.affiliation: Service de Chimie quantique et Photophysique, Université Libre de Bruxelles, CP 160/09, 50 Avenue F.D. Roosevelt, B-1050 Bruxelles, Belgium, Unité de Bioinformatique génomique et structurale, Université Libre de Bruxelles, CP 165/61, 50 Avenue F.D. Roosevelt, Institut de Pharmacie, B-1050 Bruxelles, Belgium, and Service de Chimie générale, Université Libre de Bruxelles, CP 206/04, Bld du Triomphe, B-1050 Bruxelles, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Biot