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.