Abstract：
:Grass weed populations resistant to acetyl-CoA carboxylase-inhibiting (ACCase; EC 6.4.1.2) herbicides represent a major problem for the sustainable development of modern agriculture. In the present study, extensive computational simulations, including homology modeling, molecular dynamics (MD) simulations, and molecular mechanics-Poisson-Boltzmann surface area (MM/PBSA) calculations, have been carried out to uncover the detailed molecular mechanism of Alopecurus myosuroides resistance to clodinafop, a commercial herbicide targeting ACCase. All the computational model and energetic results indicated that W374C, I388N, D425G, and G443A mutations have great effects on the conformational change of the binding pocket and the hydrogen-bonding interactions. The pi-pi interaction between ligand and the residue of Phe377 and Tyr161', playing an important contribution to the binding affinity, were decreased after mutations. In addition, the hydrogen-bonding interactions between clodinafop and the residues (Ile158' and Ala54') disappeared or decreased significantly upon mutation. As a result, the mutant-type ACCase has a lower affinity for the inhibitor binding than the wild-type enzyme, which accounts for the molecular basis of herbicidal resistance. The structural and mechanistic insights obtained from the present study will provide a valuable clue for future designing of a promising inhibitor to reduce drug resistance associated with both active and nonactive site mutations.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Zhu XL,Ge-Fei H,Zhan CG,Yang GFdoi
10.1021/ci900174dsubject
Has Abstractpub_date
2009-08-01 00:00:00pages
1936-43issue
8eissn
1549-9596issn
1549-960Xjournal_volume
49pub_type
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