Azadirachtin(A) Distinctively Modulates Subdomain 2 of Actin – Novel Mechanism to Induce Depolymerization revealed by Molecular Dynamics Study

Azadirachtin(A) (AZA) a potential insecticide from neem binds to actin and induces depolymerization in Drosophila. AZA binds to the pocket same as that of Latrunculin A (LAT) but LAT inhibits actin polymerization by stiffening the actin structure and affects the ADP-ATP exchange. The mechanism by which AZA induces actin depolymerization is not clearly understood. Therefore, different computational experiments were conducted to delineate the precise mechanism of AZA induced actin depolymerization. Molecular dynamics studies showed that AZA strongly interacted with subdomain 2 and destabilised the interactions between subdomain 2 of one actin and subdomain 1 & 4 of the adjacent actin, causing the separation of actin subunits. The separation was observed between subdomain 3 of subunit n and subdomain 4 of subunit n+2. However, the specific triggering point for the separation of the subunits was the destabilisation of direct interactions between subdomain 2 of subunit n (Arg39, Val45, Gly46 and Arg62) and subdomain 4 of subunit n+2 (Asp286, Ile287, Asp288, Ile289, Asp244 and Lys291). These results reveal a unique mechanism of an actin filament modulator that induces depolymerization. This mechanism of AZA can be used to design similar molecules against mammalian actins for cancer therapy.