The structural features and molecular-interaction properties of thiamethoxam (THA) and clothianidin (CLO) - two neonicotinoids - have been investigated through a combined approach based on a wide range of molecular modeling methods and X-ray-structure observations. Despite their close chemical structures, significant differences are emphasized by QM (DFT), docking, molecular dynamics, and QM/QM' calculations. Thus, for the first time, their propensity to interact through chalcogen-bond interactions is highlighted. The influence of the surroundings on this behavior is pointed out: in CLO, an intramolecular S⋅⋅⋅N chalcogen bond is shown to stabilize the structure in the solid state whereas the interaction leads to the preferred conformations in the isolated and continuum solvent models for both compounds. Interestingly, this interaction potential appears to be used for their binding to Ac-AChBP through intermolecular S⋅⋅⋅O chalcogen bonds with the hydroxyl group of Tyr195. The use of a suitable level of theory to describe properly these interactions is underlined, the classical methods being unsuited to highlight these interactions. The contribution of halogen bonding through the chlorine atom of the chlorothiazole ring in the binding of the two compounds is also underlined, both in the solid state and in the Ac-AChBP surroundings. However, the accommodation of the two insecticides in the binding site leads to the fact that a halogen-bond contribution is pointed out only for CLO.
Keywords: chalcogen bonding; halogen bonding; insects; molecular modeling; neonicotinoids.
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