Sarcin/Ricin Domain RNA Retains Its Structure Better Than A‑RNA in Adaptively Biased Molecular Dynamics Simulations

Less than one in thirty of the RNA
sequences transcribed in humans
are translated into protein. The noncoding RNA (ncRNA) functions in
catalysis, structure, regulation, and more. However, for the most
part, these functions are poorly characterized. RNA is modular and
described by motifs that include helical A-RNA with canonical Watson–Crick
base-pairing as well as structures with only noncanonical base pairs.
Understanding the structure and dynamics of motifs will aid in deciphering
functions of specific ncRNAs. We present computational studies on
a standard sarcin/ricin domain (SRD), citrus bark cracking viroid
SRD, as well as A-RNA. We have applied enhanced molecular dynamics
techniques that construct an inverse free-energy surface (iFES) determined
by collective variables that monitor base-pairing and backbone conformation.
Each SRD RNA is flanked on each side by A-RNA, allowing comparison
of the behavior of these motifs in the same molecule. The RNA iFESs
have single peaks, indicating that the combined motifs should denature
as a single cohesive unit, rather than by regional melting. Local
root-mean-square deviation (RMSD) analysis and communication propensity
(CProp, variance in distances between residue pairs) reveal distinct
motif properties. Our analysis indicates that the standard SRD is
more stable than the viroid SRD, which is more stable than A-RNA.
Base pairs at SRD to A-RNA transitions have limited flexibility. Application
of CProp reveals extraordinary stiffness of the SRD, allowing residues
on opposite sides of the motif to sense each other’s motions.