The elementary modules of RNA architecture in RNA evolution

Nucleic acids are characterized by the formation of hydrogen bonded pairs between the nucleotide bases along the polymer. All base-base interactions present in nucleic acids can be classified in twelve families where each family is a 4x4 matrix of the bases A, G, C, U. The usual Watson-Crick pairs belong to one of these families and the other eleven families gather the non-Watson-Crick pairs. This classification clarifies RNA architecture. Thus, RNA architecture can be viewed as the result from the hierarchical assembly of preformed double-stranded helices defined by Watson-Crick base pairs and RNA motifs maintained by non-Watson-Crick base pairs. The geometrical constraints attached to each family explain the surprising molecular neutrality observed in sequences and structures during biological evolution. This complicates the search of functional RNAs in genomes and dilutes the links between RNA structure and evolution. For RNA folding, where specificity is a requirement, global, positional and orientational, constraints on the native fold must occur upstream in the folding process. Critical parameters are the lengths of the helices, the co-axiality of the helical stacks, and the structure adopted at the junctions of helices. The molecular neutrality present in the local interactions is partially compensated by these global topological criteria, much less accessible to sequence analysis since they are attached to the three-dimensional architecture. The search for functional RNAs in genomes is thereby complexified through this dilution of the direct links between sequences and structures. During in vivo co-transcriptional, ambiguities in folding due to the neutrality of interactions and alternative pairings may be resolved during the transcription process itself by modulating transcription speed and pausing sites.

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