Determination of the Association between Mesotrione Sensitivity and Conformational Change of 4-Hydroxyphenylpyruvate Dioxygenase via Free-Energy Analyses

Onewidely known herbicide target is 4-hydroxyphenylpyruvate dioxygenase(HPPD). Avena sativa HPPD is less sensitiveto mesotrione (herbicide) than Arabidopsis thaliana HPPD. HPPD inhibitor-sensitivity is governed by the dynamic behaviorof the C-terminal alpha-helix of HPPD (H11) in closed and open forms.However, the specific relationship between the plant inhibitor sensitivityand H11 dynamic behavior remains unclear. Herein, we determined theconformational changes in H11 to understand the inhibitor-sensitivitymechanism based on free-energy calculations using molecular dynamicssimulations. The calculated free-energy landscapes revealed that Arabidopsis thaliana HPPD preferred the open formof H11 in the apo form and the closed-like form in complex with mesotrione,whereas Avena sativa HPPD exhibitedthe opposite tendency. We also identified some important residuesinvolved in the dynamic behavior of H11. Therefore, inhibitor sensitivityis governed by indirect interactions due to the protein flexibilitycaused by the conformational changes of H11.

Automated summary

This study revealed the relationship between the dynamic behavior of the C-terminal alpha-helix of 4-hydroxyphenylpyruvate dioxygenase (HPPD) and inhibitor sensitivity through free-energy calculations using molecular dynamics simulations. The results showed that Arabidopsis thaliana HPPD preferred the open form of H11 in the absence of the ligand and the closed-like form in complex with mesotrione, while Avena sativa HPPD exhibited the opposite tendency. Important amino acid residues involved in the dynamic behavior of H11 were also identified.