A Comprehensive Survey on the Nature of Ring:Ring Nucleobase Stacking Interactions in RNA: Occurrence, Structural Variability and Classification of the Associated Contacts

Abstract

The astonishing diversity in folding patterns of RNA 3D structures is crafted by myriads of noncovalent contacts, of which base pairing and stacking are the most prominent. Although the classification scheme proposed by Leontis and Westhof (RNA (2001), 7, 499) has been widely accepted for the annotation of RNA base pairs, the absence of an unambiguous classification system for base stacks appears to be a roadblock for exploring the stacking diversity in RNA. Here we provide an unambiguous and structurally-intuitive scheme for a geometry cum topology based classification of base stacking, where a stack is essentially classified in terms of the topology of the interacting nucleobase faces and the geometry described by the relative orientation of the glycosidic bonds. For heterodimeric stacks, this generates eight basic stacking geometric families, whereas for homodimeric stacks, this generates six of those. Further annotation in terms of the identity of the bases and the region of involvement of purines (5-membered, 6-membered or both rings), leads to the enumeration of 384 distinct RNA base stacks. Based on our classification scheme, we also present an algorithm for automated identification of stacks in RNA crystal structures. Overall, the work described here is expected to greatly facilitate structure-based RNA research.