title: Azadirachtin(A) distinctively modulates subdomain 2 of actin - novel mechanism to induce depolymerization revealed by molecular dynamics study.
abstract: 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 destabilized the interactions between subdomain 2 of one actin and subdomains 1 and 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 destabilization 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.
authors.affiliation: a Department of Research and Development , Bharathiar University , Coimbatore , India.|b Department of Computational Biology , Polyclone Bioservices , Bangalore , India.
authors.forename: R
authors.initials: R
authors.lastname: Pravin Kumar
authors.affiliation: c Department of Biotechnology , Mount Carmel College , Bangalore , India.
authors.forename: L
authors.initials: L
authors.lastname: Roopa
authors.affiliation: d Department of Botany , Government Arts College , Coimbatore , India.
authors.forename: M M
authors.initials: MM
authors.lastname: Sudheer Mohammed
authors.affiliation: e Polyclone Bioservices , Bangalore , India.
authors.forename: Naveen
authors.initials: N
authors.lastname: Kulkarni
mesh_terms: D000199:Actins / Q000737:chemistry*; D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D036701:Limonins / Q000737:chemistry*; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D000072417:Protein Domains; D055503:Protein Multimerization
chemical_list: D000199:Actins; D036701:Limonins; D000255:Adenosine Triphosphate; C010329:azadirachtin
keywords: DNase I-binding; actin; azadirachtin; intermolecular energy; molecular dynamics; motional correlation