Non-canonical base pairing

Non-canonical base pairs are planar, hydrogen-bonded pairs of nucleobases with hydrogen-bonding patterns that differ from those of standard Watson–Crick base pairs found in the classic double-helical structure of DNA. Although non-canonical pairs can occur in both DNA and RNA, they primarily form stable structures in RNA, where they contribute to its structural diversity and functional complexity. In DNA, such base pairs are typically transient and arise during processes like DNA replication.

Each nucleobase presents a unique distribution of hydrogen bond donors and acceptors across three edges: the Watson–Crick edge, the Hoogsteen edge (or C-H edge in pyrimidines), and the sugar edge. Canonical base pairs form through hydrogen bonding along the Watson–Crick edges, while non-canonical pairs often involve the Hoogsteen or sugar edges.

Common types of non-canonical base pairs in RNA include the G:U wobble pair, sheared G:A pair, reverse Hoogsteen A:U pair, and G:A imino pair. Together, these alternative pairings account for roughly one-third of all base pairs in functional RNA structures. The G:U wobble pair, in particular, is abundant in tRNA anticodon loops and facilitates flexible codon recognition. Sheared G:A and reverse Hoogsteen A:U pairs commonly stabilize loops, junctions, and recurrent 3D motifs such as GNRA tetraloops.

Non-canonical base pairs are often located in loops, bulges, and junctions of RNA, where they help stabilize three-dimensional structures and mediate tertiary interactions. They play critical roles in RNA folding, molecular recognition, and catalysis.