Molecular recognition of thiaclopride by Aplysia californica AChBP: new insights from a computational investigation

Abstract

The binding of thiaclopride (THI), a neonicotinoid insecticide, with Aplysia californica acetylcholine binding protein (Ac-AChBP), the surrogate of the extracellular domain of insects nicotinic acetylcholine receptors, has been studied with a QM/QM' hybrid methodology using the ONIOM approach (M06-2X/6-311G(d):PM6). The contributions of Ac-AChBP key residues for THI binding are accurately quantified from a structural and energetic point of view. The importance of water mediated hydrogen-bond (H-bond) interactions involving two water molecules and Tyr55 and Ser189 residues in the vicinity of the THI nitrile group, is specially highlighted. A larger stabilization energy is obtained with the THI-Ac-AChBP complex compared to imidacloprid (IMI), the forerunner of neonicotinoid insecticides. Pairwise interaction energy calculations rationalize this result with, in particular, a significantly more important contribution of the pivotal aromatic residues Trp147 and Tyr188 with THI through CH···π/CH···O and π-π stacking interactions, respectively. These trends are confirmed through a complementary non-covalent interaction (NCI) analysis of selected THI-Ac-AChBP amino acid pairs.

Binding of Sulfoxaflor to Aplysia californica-AChBP: Computational Insights from Multiscale Approaches

“…Remarkably, however, the main stabilization is due in both cases to the Trp147 residue, from about −65 and −61 kJ mol –1 , respectively, for SS and RR isomers, in agreement with the major role played by this amino acid in the function of nAChRs . Another interesting common point is that, as was previously pointed out for THI and the above structural parameters, the water molecules appear as important contributors in the anchoring of the two fragments (pyridine ring and nitrile moiety) of SFX, with energetic contribution ranging from −16.7 to −30.7 kJ mol –1 for both isomers. In that respect, it is worth noting that the two water molecules in the vicinity of the nitrile nitrogen appear more tightly bound (average values of −30.0 and −24.0 kJ mol –1 for SS and RR ) than the one hydrogen-bonded to the pyridine ring (values of −16.5 and −22.8 kJ mol –1 for SS and RR ).…”

“…A common feature observed for the two most stabilized isomers is the role played by the water molecules in the vicinity of the nitrile group. Indeed, a remarkable HB network involving two water molecules is structured around the nitrile nitrogen, as observed with the nitrile containing insecticides (THI and ACE) . However, the functional groups, and amino acid residues engaged in these interactions, are different according to the isomer considered.…”

“…Relevant constraints were applied for "key" hydrogen bonds, (especially between the nitrile group of SFX and the water molecule), similar to the procedure we used recently for THI. 38 For the sake of comparison and to check the quality of the final models, the average SFX-AChBP MD structures have been compared to the corresponding relevant agonist-Ac-AChBP crystallographic (thiacloprid, 3C84) structures through the calculation of RMSDs, taking into account, for the protein, the backbone atoms and, for the ligands, the heavy atoms. The pairwise interaction energies were calculated by selecting SFX and the respective binding site residues.…”

Partial Agonist Activity of Neonicotinoids on Rat Nicotinic Receptors: Consequences over Epinephrine Secretion and In Vivo Blood Pressure

“…These are also the same residues which have been found on structures of NIC bound to the 4 2 receptor (PDB entry 6CNK, 6CNJ, 5KXI) and to the 3 4 receptor (PDB entry 6PV7). In these structures, we find the cation/ bond with the trp of loop B, as well as the proximity of the residues of loops C, A, D and E. This is also coherent with recent studies of the interaction of neonicotinoids with the ACh/NIC binding site on AChBP [ 84 , 85 ]. We conclude that the binding site is identical for NIC and for neonicotinoids, the cation/ interaction being a strong marker of NIC (and ACh) binding to nAChRs.…”

Tri- and difluoromethoxylated N-based heterocycles − Synthesis and insecticidal activity of novel F3CO- and F2HCO-analogues of Imidacloprid and Thiacloprid

“…While it has been difficult to obtain crystals of any nAChR of sufficient quality to conduct high-resolution X-ray crystallography, both the crystal structure of a soluble homopentameric acetylcholine binding protein isolated from the seawater mollusc Aplysia californica (Ac-AChBP) and the only recently added crystal structure of the human a4b2 acetylcholine receptor [27] can be used to provide considerable support to the understanding of ligandreceptor interactions [28]. Figure 2 compares the mode of binding of Imidacloprid and its 6difluoromethoxy-analogue ( 15) as well as Thiacloprid and its 6-trifluoromethoxy-analogue (9) to Ac-AChBP from A. californica.…”