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WIREs RNA
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An introduction to recurrent nucleotide interactions in RNA

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RNA secondary structure diagrams familiar to molecular biologists summarize at a glance the folding of RNA chains to form Watson–Crick paired double helices. However, they can be misleading: First of all, they imply that the nucleotides in loops and linker segments, which can amount to 35% to 50% of a structured RNA, do not significantly interact with other nucleotides. Secondly, they give the impression that RNA molecules are loosely organized in three‐dimensional (3D) space. In fact, structured RNAs are compactly folded as a result of numerous long‐range, sequence‐specific interactions, many of which involve loop or linker nucleotides. Here, we provide an introduction for students and researchers of RNA on the types, prevalence, and sequence variations of inter‐nucleotide interactions that structure and stabilize RNA 3D motifs and architectures, using Escherichia coli (E. coli) 16S ribosomal RNA as a concrete example. The picture that emerges is that almost all nucleotides in structured RNA molecules, including those in nominally single‐stranded loop or linker regions, form specific interactions that stabilize functional structures or mediate interactions with other molecules. The small number of noninteracting, ‘looped‐out’ nucleotides make it possible for the RNA chain to form sharp turns. Base‐pairing is the most specific interaction in RNA as it involves edge‐to‐edge hydrogen bonding (H‐bonding) of the bases. Non‐Watson–Crick base pairs are a significant fraction (30% or more) of base pairs in structured RNAs. WIREs RNA 2015, 6:17–45. doi: 10.1002/wrna.1258 This article is categorized under: RNA Structure and Dynamics > RNA Structure, Dynamics, and Chemistry
Comparison of interactions formed by nucleotides in loops versus helices in 16S rRNA. Histogram comparing number of annotated interactions (base‐pairing, base‐stacking, and base–phosphate) formed by nucleotides in loops (blue) versus helices (red).
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Comparison of base pairs formed by nucleotides in loops versus helices in 16S rRNA. Histogram comparing number of base pairs (non‐WC as well as WC) formed by nucleotides in loops (blue) versus helices (red).
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Distribution of internal loop (IL) sizes in 16S rRNA. Histogram of IL sizes (in nts) from the 2D representation of 16S rRNA in Figure . Flanking WC basepairs are not included.
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Distribution of hairpin loop (HL) sizes in 16S rRNA. Histogram of HL sizes (in nts) from the 2D representation of 16S rRNA in Figure . Flanking WC basepairs are not included.
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Distribution of helix lengths in 16S rRNA. Histogram of helix lengths (in base pairs) from the 2D representation of 16S rRNA in Figure , using definitions of helices explained in the text.
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Structural representations of Escherichia coli (E. coli) 16S rRNA. 2D and 3D representations of 16S rRNA of E. coli, with helical elements colored identically. Lines connect WC paired nts. The 3D is PDB file 2AW7 whereas the 2D is modified from the study by Petrov et al. The multi‐helix junctions that contain embedded WC base pairs are indicated with brick‐red arrows and the paired bases with bold lines of the same color.
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(a) 3D structures of internal loop from helix 20 of 16S rRNA PDB files 2AW7 and 1FJG. (b) 2D annotations showing conserved non‐WC base pairs. Although they differ in sequence, the two motifs have the same interactions and are assigned to the same motif group. (c) Superposition of isosteric tWH and tSH non‐Watson–Crick base pairs from the Escherichia coli and Thermus thermophilus versions of the helix 20 motif, slightly shifted for visual clarity.
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Base–ribose stacking interaction. The conserved base–ribose stacking interaction involving ribose 34 in the anticodon of tRNA bound to the P‐site of 16S rRNA and conserved base G966 in 16S. The figure is a stereo‐view of the base–ribose interaction. From PDB file 4GD1.
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Base–phosphate (BPh) interactions observed in RNA 3D structures for each base. H‐bonds are indicated with dashed lines. BPh categories are numbered 0–9, starting at the H6 (pyrimidine) or H8 (purine) base positions. BPh interactions that involve equivalent functional groups on different bases are grouped together: 0 BPh (A, C, G, U), 5BPh (G, U), 6BPh (A, C), 7BPh (A, C) and 9BPh (C, U). Bridging interactions, 8BPh and 4BPh, are especially stable. Adapted from Zirbel et al. (9) with permission.
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Calculation of IsoDiscrepancy Index (IDI) to compare geometries of base pairs. The IDI is illustrated using nonisosteric base pairs. To calculate the IDI for two base pairs, the bases designated ‘first base’ in each base pair are superposed (bases on the left in each panel), and then the following three quantities are evaluated, normalized, and summed: (1) The difference, Δc, in the intra‐base pair C1′–C1′ distances, illustrated for nonisosteric cWW AG and AU. (2) The inter‐base pair C1′–C1′ distance, t1, between the C1′ atoms of the second bases of the base pairs, illustrated for the near isosteric cWW AU and AC base pairs. (3) The angle, theta, about an axis perpendicular to the base pair plane, required to superpose the second bases, illustrated using nonisosteric cWW AU and cWS AU base pairs. Adapted from Stombaugh et al. (3) with permission.
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Representative base pairs. UA base combination in four different base‐pairing geometries: (a) cis Watson–Crick/Watson–Crick (cWW); (b) trans Watson–Crick/Watson–Crick (tWW); (c) cis Watson–Crick/Hoogsteen (cWH); and (d) trans Watson–Crick/Hoogsteen (cWH).
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G and C nucleotides to print on transparencies. U and A nts in two orientations to print on transparencies for making base pairs in different geometries by juxtaposing H‐bonding donor (blue) and acceptor (red) groups.
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U and A nucleotides to print on transparencies. U and A nts in two orientations to print on transparencies for making base pairs in different geometries by juxtaposing H‐bonding donor (blue) and acceptor (red) groups.
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Structures of RNA nucleotides. RNA nts G, C, A, and U each have three edges along which H‐bonding takes place. Hoogsteen (H), Watson–Crick (W), and sugar (S) edges are marked with dotted lines. Base ring atoms are numbered from 1 to 9 for purines and 1 to 6 for pyrimidines. Ribose carbons are numbered 1′ to 5′. Exocyclic groups and attached hydrogens are numbered according to ring position. H‐bond donors are highlighted with blue and H‐bond acceptors with red.
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Amino Acid interactions for loop versus helix nucleotides. Histogram of number of amino acids within 4 Å for nucleotides in loops (blue) versus helices (red) in Escherichia coli 30S ribosome.
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Definition of crossing number for long‐range interactions. Base pairs (i, k) and (m, n) are nested in (a) but non‐nested in (b). Interaction (x, y) in (C) crosses over two nested base pairs, (i, k) and (m, n) and has crossing number equal to 2.
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