Molecular Dynamics Simulations Study on the Resistant Mechanism of Insects to Imidacloprid due to Y151-S and R81T Mutations in nAChRs

Imidacloprid (IMI) is the first widely used neonicotinoid insecticide due to its high insecticidal activity and low toxicity. However, as its extensive use in crop protection, many insects are resistant to IMI. One of the main resistance mechanisms of insects to IMI is Y151-S and R81T mutations in nicotinic acetylcholine receptor (nAChR). However, how these two mutations affect the interaction of IMI with nAChR is unknown. Here, to uncover the resistant mechanism of nAChR to IMI due to Y151-S and R81T mutations, molecular dynamics simulations and molecular mechanics/generalized Born surface area (MM-GBSA) calculation, residue interaction network (RIN) analysis were performed. Due that the structure of nAChR is still unkonwn, the crystal structure of lymnaea stagnalis acetylcholine binding protein (Ls-AChBP) was used here to simulate nAChR. Y151 and R81 in nAChR correspond to H145 and Q55 in Ls-AChBP, respectively. The calculated binding free energy indicated that two mutations reduced the binding ability of IMI with Ls-AChBP. Q55T mutation reduced the contribution of several key residues, such as W53, T55, Y113, T144 and C187. As for H145-S mutation, the contribution of W53, Q55 and Y113 residues also decreased. RIN analysis showed that two mutants changed the binding pocket by changing the conformation of residues that interact directly with the mutated residues. The obtained resistance mechanism of IMI will be helpful for the design of potent insecticides.