title: Imidacloprid and thiacloprid neonicotinoids bind more favourably to cockroach than to honeybee α6 nicotinic acetylcholine receptor: insights from computational studies.
abstract: The binding interactions of two neonicotinoids, imidacloprid (IMI) and thiacloprid (THI) with the extracellular domains of cockroach and honeybee α6 nicotinic acetylcholine receptor (nAChR) subunits in an homomeric receptor have been studied through docking and molecular dynamics (MD) simulations. The binding mode predicted for the two neonicotinoids is validated through the good agreement observed between the theoretical results with the crystal structures of the corresponding complexes with Ac-AChBP, the recognized structural surrogate for insects nAChR extracellular ligand binding domain. The binding site of the two insect α6 receptors differs by only one residue of loop D, a serine residue (Ser83) in cockroach being replaced by a lysine residue (Lys108) in honeybee. The docking results show very close interactions for the two neonicotinoids with both α6 nAChR models, in correspondence to the trends observed in the experimental neonicotinoid-Ac-AChBP complexes. However, the docking parameters (scores and energies) are not significantly different between the two insect α6 nAChRs to draw clear conclusions. The MD results bring distinct trends. The analysis of the average interaction energies in the two insects α6 nAChRs shows indeed better affinity of neonicotinoids bound to α6 cockroach compared to honeybee nAChR. This preference is explained by tighter contacts with aromatic residues (Trp and Tyr) of the binding pocket. Interestingly, the non-conserved residue Lys108 of loop D of α6 honeybee nAChR interacts through van der Waals contacts with neonicotinoids, which appear more favourable than the direct or water mediated hydrogen-bond interaction between the OH group of Ser83 of α6 cockroach nAChR and the electronegative terminal group of the two neonicotinoids (nitro in IMI and cyano in THI). Finally, in both insects nAChRs, THI is consistently found to bind more favourably than IMI.
authors.affiliation: Université de Nantes, UMR CNRS 6230, Chimie Et Interdisciplinarité: Synthèse, Analyse, Modélisation (CEISAM), UFR des Sciences et des Techniques, 2, rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France. Electronic address: balaji.panneerselvam@univ-nantes.fr.
authors.forename: Balaji
authors.initials: B
authors.lastname: Selvam
authors.affiliation: Université de Nantes, UMR CNRS 6230, Chimie Et Interdisciplinarité: Synthèse, Analyse, Modélisation (CEISAM), UFR des Sciences et des Techniques, 2, rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Graton
authors.affiliation: Université de Nantes, UMR CNRS 6230, Chimie Et Interdisciplinarité: Synthèse, Analyse, Modélisation (CEISAM), UFR des Sciences et des Techniques, 2, rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France.
authors.forename: Adèle D
authors.initials: AD
authors.lastname: Laurent
authors.affiliation: Université de Nantes, UMR CNRS 6230, Chimie Et Interdisciplinarité: Synthèse, Analyse, Modélisation (CEISAM), UFR des Sciences et des Techniques, 2, rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France.
authors.forename: Zakaria
authors.initials: Z
authors.lastname: Alamiddine
authors.affiliation: Université de Nantes, UMR CNRS 6230, Chimie Et Interdisciplinarité: Synthèse, Analyse, Modélisation (CEISAM), UFR des Sciences et des Techniques, 2, rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Mathé-Allainmat
authors.affiliation: Université de Nantes, UMR CNRS 6230, Chimie Et Interdisciplinarité: Synthèse, Analyse, Modélisation (CEISAM), UFR des Sciences et des Techniques, 2, rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Lebreton
authors.affiliation: Université d'Angers, Récepteurs et Canaux Ioniques Membranaires, UPRES EA 2647, USC INRA 2023, UFR Sciences, 2 boulevard Lavoisier, 49045 Angers Cedex, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Coqueret
authors.affiliation: Université d'Angers, Récepteurs et Canaux Ioniques Membranaires, UPRES EA 2647, USC INRA 2023, UFR Sciences, 2 boulevard Lavoisier, 49045 Angers Cedex, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Olivier
authors.affiliation: Centre de Recherche en Cancérologie Nantes-Angers, UMR_S 892 - C 6299, Institut de Recherche en Santé IRS Université de Nantes, Unité INSERM 892 - CNRS 6299 Centre de Recherche en Cancérologie Nantes-Angers, 8 quai Moncousu, BP70721, 44007 Nantes Cedex, France.
authors.forename: Steeve H
authors.initials: SH
authors.lastname: Thany
authors.affiliation: Université de Nantes, UMR CNRS 6230, Chimie Et Interdisciplinarité: Synthèse, Analyse, Modélisation (CEISAM), UFR des Sciences et des Techniques, 2, rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France. Electronic address: jean-yves.le-questel@univ-nantes.fr.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Le Questel
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001516:Bees / Q000737:chemistry*; D001665:Binding Sites; D003058:Cockroaches / Q000737:chemistry*; D017124:Conserved Sequence; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D000073943:Neonicotinoids; D009574:Nitro Compounds / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D016415:Sequence Alignment; D040681:Structural Homology, Protein; D013816:Thermodynamics; D013843:Thiazines / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D007093:Imidazoles; D000073943:Neonicotinoids; D009574:Nitro Compounds; D011725:Pyridines; D011978:Receptors, Nicotinic; D013843:Thiazines; C104518:nicotinic receptor alpha6; C082359:imidacloprid; C417209:thiacloprid
keywords: Docking; Homology model; Molecular dynamics simulations; Neonicotinoids; nAChRs