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Geometric nomenclature and classification of RNA base pairs
- NEOCLES B. LEONTIS, ERIC WESTHOF
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Non-Watson–Crick base pairs mediate specific interactions responsible for RNA–RNA self-assembly and RNA–protein recognition. An unambiguous and descriptive nomenclature with well-defined and nonoverlapping parameters is needed to communicate concisely structural information about RNA base pairs. The definitions should reflect underlying molecular structures and interactions and, thus, facilitate automated annotation, classification, and comparison of new RNA structures. We propose a classification based on the observation that the planar edge-to-edge, hydrogen-bonding interactions between RNA bases involve one of three distinct edges: the Watson–Crick edge, the Hoogsteen edge, and the Sugar edge (which includes the 2′-OH and which has also been referred to as the Shallow-groove edge). Bases can interact in either of two orientations with respect to the glycosidic bonds, cis or trans relative to the hydrogen bonds. This gives rise to 12 basic geometric types with at least two H bonds connecting the bases. For each geometric type, the relative orientations of the strands can be easily deduced. High-resolution examples of 11 of the 12 geometries are presently available. Bifurcated pairs, in which a single exocyclic carbonyl or amino group of one base directly contacts the edge of a second base, and water-inserted pairs, in which single functional groups on each base interact directly, are intermediate between two of the standard geometries. The nomenclature facilitates the recognition of isosteric relationships among base pairs within each geometry, and thus facilitates the recognition of recurrent three-dimensional motifs from comparison of homologous sequences. Graphical conventions are proposed for displaying non-Watson–Crick interactions on a secondary structure diagram. The utility of the classification in homology modeling of RNA tertiary motifs is illustrated.
Conserved geometrical base-pairing patterns in RNA
- NEOCLES B. LEONTIS, ERIC WESTHOF
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- Quarterly Reviews of Biophysics / Volume 31 / Issue 4 / November 1998
- Published online by Cambridge University Press:
- 01 November 1998, pp. 399-455
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1. INTRODUCTION 399
2. DEFINITIONS 401
3. CIS BASEPAIRS 410
3.1 Cis Watson–Crick/Watson–Crick 410
3.2 Wobble pairings 411
3.3 Cis Watson–Crick/Hoogsteen pairings 416
3.4 Bifurcated pairings 417
3.5 Cis open and water-inserted 421
4. TRANS BASEPAIRS 423
4.1 Trans Watson–Crick/Watson–Crick 423
4.2 Trans wobble pairs 424
4.3 Trans Watson–Crick/Hoogsteen pairs 424
4.4 Trans Hoogsteen/Hoogsteen pairs 430
4.5 Trans bifurcated pairings 432
5. SHALLOW-GROOVE PAIRINGS 432
5.1 Hoogsteen/Shallow-groove pairs 433
5.2 Watson–Crick/Shallow-groove pairings 438
5.3 Shallow-groove/Shallow-groove pairings 440
6. SIDE-BY-SIDE BASES 446
7. DEFINING A LIBRARY OF ISOSTERIC PAIRINGS 446
8. CONCLUSIONS 451
9. ACKNOWLEDGEMENTS 452
10. REFERENCES 452
RNA molecules fold into a bewildering variety of complex 3D structures. Almost every new RNA structure obtained at high resolution reveals new, unanticipated structural motifs, which we are rarely able to predict at the current stage of our theoretical understanding. Even at the most basic level of specific RNA interactions – base-to-base pairing – new interactions continue to be uncovered as new structures appear. Compilations of possible non-canonical base-pairing geometries have been presented in previous reviews and monographs (Saenger, 1984; Tinoco, 1993). In these compilations, the guiding principle applied was the optimization of hydrogen-bonding. All possible pairs with two standard H-bonds were presented and these were organized according to symmetry or base type. However, many of the features of RNA base-pairing interactions that have been revealed by high-resolution crystallographic analysis could not have been anticipated and, therefore were not incorporated into these compilations. These will be described and classified in the present review. A recently presented approach for inferring basepair geometry from patterns of sequence variation (Gautheret & Gutell, 1997) relied on the 1984 compilation of basepairs (Saenger, 1984), and was extended to include all possible single H-bond combinations not subject to steric clashes. Another recent review may be consulted for a discussion of the NMR spectroscopy and thermodynamic effects of non-canonical (‘mismatched’) RNA basepairs on duplex stability (Limmer, 1997).
The 5S rRNA loop E: Chemical probing and phylogenetic data versus crystal structure
- NEOCLES B. LEONTIS, ERIC WESTHOF
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A significant fraction of the bases in a folded, structured RNA molecule participate in noncanonical base pairing interactions, often in the context of internal loops or multi-helix junction loops. The appearance of each new high-resolution RNA structure provides welcome data to guide efforts to understand and predict RNA 3D structure, especially when the RNA in question is a functionally conserved molecule. The recent publication of the crystal structure of the “Loop E” region of bacterial 5S ribosomal RNA is such an event [Correll CC, Freeborn B, Moore PB, Steitz TA, 1997, Cell 91:705–712]. In addition to providing more examples of already established noncanonical base pairs, such as purine–purine sheared pairings, trans-Hoogsteen UA, and GU wobble pairs, the structure provides the first high-resolution views of two new purine–purine pairings and a new GU pairing. The goal of the present analysis is to expand the capabilities of both chemical probing and phylogenetic analysis to predict with greater accuracy the structures of RNA molecules. First, in light of existing chemical probing data, we investigate what lessons could be learned regarding the interpretation of this widely used method of RNA structure probing. Then we analyze the 3D structure with reference to molecular phylogeny data (assuming conservation of function) to discover what alternative base pairings are geometrically compatible with the structure. The comparisons between previous modeling efforts and crystal structures show that the intricate involvements of ions and water molecules in the maintenance of non-Watson–Crick pairs render the process of correctly identifying the interacting sites in such pairs treacherous, except in cases of trans-Hoogsteen A/U or sheared A/G pairs for the adenine N1 site. The phylogenetic analysis identifies A/A, A/C, A/U and C/A, C/C, and C/U pairings isosteric with sheared A/G, as well as A/A and A/C pairings isosteric with both G/U and G/G bifurcated pairings. Thus, each non-Watson–Crick pair could be characterized by a phylogenetic signature of variations between isosteric-like pairings. In addition to the conservative changes, which form a dictionary of pairings isosterically compatible with those observed in the crystal structure, concerted changes involving several base pairs also occur. The latter covariations may indicate transitions between related but distinctive motifs within the loop E of 5S ribosomal RNA.