title: Using Surface Scans for the Evaluation of Halogen Bonds toward the Side Chains of Aspartate, Asparagine, Glutamate, and Glutamine.
abstract: Using halogen-specific Connolly type molecular surfaces, we herein invented a new type of surface-based interaction analysis employed for the study of halogen bonding toward model systems of biologically relevant carboxylates (ASP/GLU) and carboxamides (ASN/GLN). Database mining and statistical assessment of the PDB revealed that such interactions are widely underrepresented at the moment. We observed important distance-dependent adaptions of the binding modes of halobenzenes from a preferential oxygen-directed to a bifurcated interaction geometry of the carboxylate. In addition, halogen···π contacts perpendicular to the nitrogen atom of the carboxamide become increasingly important for the lighter halogens. Our analysis on a MP2/TZVPP level of theory is backed by CCSD(T)/CBS reference calculations. To put the vast interaction energies into perspective, we also performed COSMO-RS calculations of the solvation free energy. Facilitating the visualization of our results mapped onto any binding site of choice, we aim to inspire more design studies showcasing these underrepresented interactions.
authors.affiliation: Laboratory for Molecular Design and Pharmaceutical Biophysics, Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard-Karls-University Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.|Center for Bioinformatics Tübingen (ZBIT), Eberhard Karls Universität Tübingen , Sand 1, 72076 Tübingen, Germany.
authors.forename: Markus O
authors.initials: MO
authors.lastname: Zimmermann
authors.affiliation: Laboratory for Molecular Design and Pharmaceutical Biophysics, Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard-Karls-University Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.|Center for Bioinformatics Tübingen (ZBIT), Eberhard Karls Universität Tübingen , Sand 1, 72076 Tübingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lange
authors.affiliation: Physikalisch-Chemisches Institut, Justus-Liebig-Universität Gießen , Heinrich-Buff-Ring 17, 35392 Gießen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zahn
authors.affiliation: Laboratory for Molecular Design and Pharmaceutical Biophysics, Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard-Karls-University Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.|Center for Bioinformatics Tübingen (ZBIT), Eberhard Karls Universität Tübingen , Sand 1, 72076 Tübingen, Germany.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Exner
authors.affiliation: Laboratory for Molecular Design and Pharmaceutical Biophysics, Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard-Karls-University Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.|Center for Bioinformatics Tübingen (ZBIT), Eberhard Karls Universität Tübingen , Sand 1, 72076 Tübingen, Germany.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Boeckler
mesh_terms: D000577:Amides / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry*; D001216:Asparagine / Q000737:chemistry; D001224:Aspartic Acid / Q000737:chemistry; D002264:Carboxylic Acids / Q000737:chemistry; D018360:Crystallography, X-Ray; D015195:Drug Design; D018698:Glutamic Acid / Q000737:chemistry; D005973:Glutamine / Q000737:chemistry; D006219:Halogens / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D012997:Solvents / Q000737:chemistry
chemical_list: D000577:Amides; D000596:Amino Acids; D002264:Carboxylic Acids; D006219:Halogens; D012997:Solvents; D005973:Glutamine; D001224:Aspartic Acid; D018698:Glutamic Acid; D001216:Asparagine