Cristian Micheletti

Physical models for the degradation resistance of viral genomic RNAs

RNA genomes of Zika and other flaviviruses contain short pseudoknotted elements that protect them from exonuclease degradation. These elements, known as xrRNAs, are ca 80-nucleotide long and have a non-specific resistance to exonucleases. To clarify the physical basis of the latter, we modeled the enzymatic degradation of Zika xrRNA as a driven translocation through a cylindrical pore. We studied the process using implicit-solvent atomistic simulations with a native-centric force field. We observed a dramatic directional resistance to translocation, with a significantly higher activation barrier at the 5' end compared to the 3' one. The remarkable directional effect originates from the way that mechanical tension propagates in the pseudoknotted xrRNAs, and can account for the observed degradation resistance [1]. Our study further establishes that nanopore setups could harness the time-resolved profile of translocation velocity, which is non-uniform and directional-dependent, to infer the secondary and tertiary organization of RNAs [1,2].

[1] A. Suma, L. Coronel, G. Bussi and C. Micheletti, Nature Commun. 11, 3749 (2020)

[2] M. Becchi, P. Chiarantoni and C. Micheletti, J. Phys. Chem. B 125, 1098-1196 (2021)