Directional translocation resistance of Zika xrRNA

Abstract

xrRNAs from flaviviruses survive in host cells for their exceptional dichotomic response to the unfolding action of different enzymes. They can be unwound, and hence copied, by replicases, and yet can resist degradation by exonucleases. How the same stretch of xrRNA can encode such diverse responses is an open question. Here, by using atomistic models and translocation simulations, we uncover an elaborate and directional mechanism for how stress propagates when the two xrRNA ends, 5 and 3 , are driven through a pore. Pulling the 3 end, as done by replicases, elicits a progressive unfolding; pulling the 5 end, as done by exonucleases, triggers a counterintuitive molecular tightening. Thus, in what appears to be a remarkable instance of intra-molecular tensegrity, the very pulling of the 5 end is what boosts resistance to translocation and consequently to degradation. The uncovered mechanistic principle might be co-opted to design molecular meta-materials.

RNA Pore Translocation with Static and Periodic Forces: Effect of Secondary and Tertiary Elements on Process Activation and Duration

“…Following ref. 8, the 5 and the 3 xrRNA ends were separately primed at the entrance of a narrow cylindrical pore embedded in a parallelepiped slab, see Fig. 1a,b,e.…”

“…Following ref. 8 the system temperature and energy scale were calibrated by matching the typical stretching forces (∼15 pN) required to unfold small RNA helices at 300 K. Simulations were carried out with proper atomic masses and with default values of the friction coefficient.…”

“…Measurements of ionic current blockades in nanopores [3] have been used to sequence RNAs [4], to probe salient features of their folding pathway [5] and to detect modified nucleobases [6]. Molecular dynamics simulations have shown that driving RNAs through pores of appropriate width can relay information about their compliance to structural deformations [7] and directional mechanical resistance [8].…”

“…In a recent theoretical and computational study from our group [8], we used atomistic simulations of Zika xrRNA translocation to explore the microscopic origin of its resistance to degradation. The xrRNA structure, see Fig.…”

“…In our study, which adopts the same setup of ref. 8, we study how the xrRNA responds when driven from either of its ends through a narrow pore by static and periodic forces. In particular we examine the translocation duration and activation times, and discuss how they significantly vary with the magnitude and period of the driving force, and with pulling directionality, i.e.…”