Direct and Indirect Influence of Amino Acid Substitution in Acetyl-Coenzyme A Carboxylase on Binding Affinity of Cyclohexanedione Oxime Herbicides.

Acetyl-coenzyme A carboxylase (ACCase) is a key herbicide target in grass species, with I1781L and D2078G mutations in the carboxyl transferase domain of plastidic ACCase conferring resistance to all ACCase inhibitor classes. The I1781L mutation was hypothesized to reduce the binding affinity of cyclohexanedione oximes (DIMs) due to increased steric hindrance at the binding site. Testing DIMs with a methyl group at the oxime carbon revealed reduced resistance in blackgrass with the I1781L mutation compared to the corresponding commercial herbicides. A correlation between the alkyl chain length and resistance factor (RF) was observed. Compound A1, featuring a methyl group, was also effective against D2078G and showed an RF of 5 or less across resistant populations, with herbicidal efficacy below 100 g a.i. ha-1. Homology modeling and molecular dynamics simulations suggest that van der Waals interactions between the ligand and specific residues in the receptor contribute to the observed change in activity.