Beyond DAD: proposing a one-letter code for nucleobase-mediated molecular recognition†

Abstract

Nucleobase binding is a fundamental molecular recognition event central to modern biological and bioinspired supramolecular research. Underpinning this recognition is a deceptively simple hydrogen-bonding code, primarily based on the canonical nucleobases in DNA and RNA. Inspired by these biotic structures, chemists and biologists have designed abiotic hydrogen-bonding motifs that can interact with, augment, and reshape native molecular recognition, for applications ranging from genetic code expansion and nucleic acid recognition to supramolecular materials utilizing mono- and bifacial nucleobases. However, as the number of nucleobase-inspired motifs expands, the absence of a standard vocabulary to describe hydrogen bond (HB) patterns has led to a haphazard mixture of shorthand descriptors that are confusing and inconsistent. Alternative notations that specify individual HB sites (such as DAD for donor–acceptor–donor) are cumbersome for biological and supramolecular constructs that contain many such patterns. This situation creates a barrier to sharing and interpreting nucleobase-related research across sub-disciplines, hindering collaboration and innovation. In this perspective, we aim to initiate discourse on this issue by considering what would be needed to formulate a concise one-letter code for the HB patterns associated with synthetic nucleobases. We first summarize some of the issues caused by the current absence of a consistent naming scheme. Subsequently, we discuss some key considerations in designing a coherent naming system. Finally, we leverage chemical rationale and pedagogical mnemonic considerations to propose a succinct and intuitive one-letter code for supramolecular two- and three-HB motifs. We hope that this discussion will spark conversations within our interdisciplinary community, thereby facilitating collaboration and easing communication among researchers engaged in synthetic nucleobase design.