Going beyond base-pairs: topology-based characterization of base-multiplets in RNA

Identification and characterization of base-multiplets, which are essentially mediated by base-pairing interactions, can provide insights into the diversity in the structure and dynamics of complex functional RNAs, and thus facilitate hypothesis driven biological research. The necessary nomenclature scheme, an extension of the geometric classification scheme for base-pairs by Leontis and Westhof, is however available only for base-triplets. In the absence of information on topology, this scheme is not applicable to quartets and higher order multiplets. Here we propose a topology-based classification scheme which, in conjunction with a graph-based algorithm, can be used for the automated identification and characterization of higher order base-multiplets in RNA structures. Here, the RNA structure is represented as a graph, where nodes represent nucleotides and edges represent base-pairing connectivity. Sets of connected components (of n nodes) within these graphs constitute subgraphs representing multiplets of “n” nucleotides. The different topological variants of the RNA multiplets thus correspond to different nonisomorphic forms of these subgraphs. To annotate RNA base-multiplets unambiguously, we propose a set of topology-based nomenclature rules for quartets, which are extendable to higher multiplets. We also demonstrate the utility of our approach toward the identification and annotation of higher order RNA multiplets, by investigating the occurrence contexts of selected examples in order to gain insights regarding their probable functional roles.