Natural RNA found in the ribosome, RNaseP, riboswitches and ribozymes has inspired the design and characterization of many synthetic RNA structures. These architectures are composed of building blocks that are comprised of RNA units that serve as modules (or motifs) for the construction of novel, structural and functional RNA molecules. To better understand the types of interactions involved in generating motifs, characterization of both the secondary and tertiary structure is essential. Large, complex RNA require many cooperative units folding in a programmable way, stabilizing the overall structure. The research presented herein, demonstrates the ability of RNA units to preserve their function despite drastic sequence variation, while still maintaining their overall shape or topology. We have identified several classes of GNRA tetraloop receptors (both natural and synthetic) that can be characterized by their phenotypic behavior toward GNRA tetraloops. Phenotypic behavior, as well as comparative analysis of known crystal structures can elucidate structural detail of unknown receptors. We have also identified additional folding constraints that can prove beneficial in structure prediction and architectonic design of large structured RNA's providing a basis for characterization and implementation of novel design principles, enhancing the complexity of synthetic RNA.