Conformational changes induced by permethrin and its metabolites on Cu-Zn superoxide dismutase: fluorescence, computational and docking results

The aim of the present study is to investigate the proclivity of permethrin and its metabolites to affect the structure and activity of Cu/Zn superoxide dismutase (SOD) by using intrinsic fluorescence and 8-ANS fluorescence techniques. Computational results and docking were used in order to assess the way of interaction at molecular level between SOD and permethrin or its metabolites. Results show that both, permethrin and its metabolites are able to induce conformational variation on SOD. Permethrin and 3-phenoxybenzyl alcohol metabolite induce a blue shift toward the hydrophobic aminoacids Leu-101, Ile-102, Leu-104, Ile-110 and Ile-111, with a significant peak increase. An opposite effect was shown by 3-phenoxy benzaldehyde and 3-phenoxybenzoic acid with a progressive reduction of tyrosine fluorescence emission, without any shift. Computational results confirm that all the molecules considered have more than one allosteric binding site but none of them interact with SOD at the catalytic Cu,Zn cleft. Moreover, all this binding poses are very close in binding energy demonstrating that there is not only a preferred interaction site but that most of them are pharmacophoric important and due to their relative energy in equilibrium with a population strictly connected the ligand concentration. All the ligands are involved in many hydrogen bonds through their polar oxygen moieties but due to the presence of a common aromatic hydrophobic core, many hydrophobic interaction are due to the SOD nature rich in apolar aminoacids. Computational results confirmed the specific interaction of permethrin and its metabolites with Tyr108, responsible of changes in fluorescence emission.