The structural plasticity of nucleic acid duplexes revealed by WAXS and MD

Abstract

Double-stranded DNA (dsDNA) and RNA (dsRNA) helices display an unusual structural diversity. Some structural variations are linked to sequence and may serve as signaling units for protein-binding partners. Therefore, elucidating the mechanisms and factors that modulate these variations is of fundamental importance. While the structural diversity of dsDNA has been extensively studied, similar studies have not been performed for dsRNA. Because of the increasing awareness of RNA’s diverse biological roles, such studies are timely and increasingly important. We integrate solution x-ray scattering at wide angles (WAXS) with all-atom molecular dynamics simulations to explore the conformational ensemble of duplex topologies for different sequences and salt conditions. These tightly coordinated studies identify robust correlations between features in the WAXS profiles and duplex geometry and enable atomic-level insights into the structural diversity of DNA and RNA duplexes. Notably, dsRNA displays a marked sensitivity to the valence and identity of its associated cations.

RNA triplex structures revealed by WAXS-driven MD simulations

“…To evaluate the correlation between structural features and WAXS signals, we construct correlation maps (Eq.11 of ref 36 ). We computed the normalized deviation between logarithmic intensities of simulated and experimental curves.…”

“…As an alternative approach, all atom models of RNAs are being successfully refined and tuned to come to agreement with experimental data acquired by NMR, [29][30][31][32][33] cryoEM 34 , solution small 35 or wide angle scattering (SWAXS). 36 A recent study that motivates this one combines the Sample and Select (SaS) approach with wide angle x-ray scattering data on RNA duplexes. 36 Results provide insight both into variations from A form structure and counterion distributions around double stranded RNA.To advance this work and to include higher order interactions, we made a similar comparison between SWAXS measurements of constructs containing multiple, stacked RNA base triples, and computed profiles of an 'ideal' triplex, subject to extended sampling.…”

“…36 A recent study that motivates this one combines the Sample and Select (SaS) approach with wide angle x-ray scattering data on RNA duplexes. 36 Results provide insight both into variations from A form structure and counterion distributions around double stranded RNA.To advance this work and to include higher order interactions, we made a similar comparison between SWAXS measurements of constructs containing multiple, stacked RNA base triples, and computed profiles of an 'ideal' triplex, subject to extended sampling. This SaS approach failed to capture the details reported in the experiment; the 'correct' structures do not appear to be present in the pool.…”

“…As an alternative approach, all atom models of RNAs are being successfully refined and tuned to come to agreement with experimental data acquired by NMR, [29][30][31][32][33] cryoEM 34 , solution small 35 or wide angle scattering (SWAXS). 36 A recent study that motivates this one combines the Sample and Select (SaS) approach with wide angle x-ray scattering data on RNA duplexes. 36 Results provide insight both into variations from A form structure and counterion distributions around double stranded RNA.…”

“…36 A recent study that motivates this one combines the Sample and Select (SaS) approach with wide angle x-ray scattering data on RNA duplexes. 36 Results provide insight both into variations from A form structure and counterion distributions around double stranded RNA.…”