A viral disease outbreak in plants can cause a scarcity of food supply and is a severe concern to humanity. The siRNA-mediated RNA-induced silencing complex (RISC) formation is a primary defense mechanism in plants against viruses, where the RISC binds and degrades the viral mRNAs. As a counter-defense, many viruses encode RNA silencing suppressor proteins (for example, the p19 protein from the Tombusviridae family) for viral proliferation in plants. The functional form of p19 (homodimer) binds to plant siRNA with high affinities, thereby interrupting the RISC formation, thus preventing the viral mRNA silencing in plants. By altering the RISC formation, the p19 protein helps the virus invasion in the plant and ultimately stunts the host growth. We designed several modified nucleic acid-based molecules for p19 inhibition in the present study. We performed all-atom explicit-solvent molecular dynamics simulations (400 ns, 3 replicas each) for control/modified RNA – p19 complexes followed by energetic estimations. Strikingly, a few modified nucleic acids not only retained the double-helical structural integrity but also displayed remarkably enhanced p19 binding compared to the control siRNA, hence the importance of designed flexible nucleic acids as p19 inhibitors for crop protection is foreseen.
- Pant, P.; Leese, F. Probing the Nucleic Acid Flexibility to Disarm the Viral Counter-Defense Machinery: Design and Characterization of Potent p19 Inhibitors. J. Phys. Chem. B. 2023, 127, 8842-8851.