Development of CHARMM compatible force field parameters and molecular dynamics simulations for the pesticide flupyradifurone

Flupyradifurone (FLU) is a novel butenolide insecticide with partial agonist activity for insect nicotinic acetylcholine receptors. Its safety for non-target organisms has been questioned in the literature, despite initial claims of its harmlessness. Detailed understanding of its toxicity and related molecular mechanisms remain under discussion. Thus, in this work, an optimized set of CHARMM compatible parameters for FLU is presented. CHARMM General Force Field program was used as a starting point while the non-bonded and bonded parameters were adjusted and optimized to reproduce MP2/6-31G(d) accuracy level results. For the validity assessment of these parameters, infrared spectrum, water-octanol partition coefficient, and normal modes were computed and compared to experimental values found in the literature. Several MD simulations of FLU in water and FLU in complex with an acetylcholine-binding protein were performed to estimate the ability of the optimized parameters to correctly describe its torsional space and reproduce observed crystallographic trends respectively. Flupyradifurone is a recently introduced nicotinic acetylcholine receptor (nAChR) competitive modulator in the insecticide market. Understanding its binding characteristics and conformational behavior is crucial for exploring its resistance and toxicity mechanisms. Accordingly, we have developed an optimized set of CHARMM compatible parameters. The reliability of these parameters is validated by the strong correlation between the theoretically computed and experimental properties. image