Chimeric XNA: An Unconventional Design for Orthogonal Informational Systems

Abstract

The paradigm of homogenous-sugar-backbone of RNA and DNA has reliably guided the construction of many functional and useful xeno nucleic acid (XNA) systems to date. Deviations from this monotonous and canonical design, in many cases, results in oligonucleotide systems that lack base pairing with themselves, or with RNA or DNA. Here we show that nucleotides of two such compromised XNA systems can be combined with RNA and DNA in specific patterns to produce chimeric-backbone oligonucleotides, which in certain cases demonstrate base pairing properties comparable to-or stronger than-canonical systems, while also altering the conventional Watson-Crick pairing behavior. The unorthodox pairing properties generated from these chimeric sugar-backbone oligonucleotides suggest a counterintuitive approach of creating modules consisting of non-base pairing XNAs with RNA/DNA in a set pattern. This strategy has the potential to increase the diversity of unconventional nucleic acids leading to orthogonal backbone-sequence-controlled informational systems.

The difficult case of an RNA-only origin of life

“…For example, nucleic acid polymers with non-inheritable backbone heterogeneities (e.g. 2 0 -5 0 versus 3 0 -5 0 backbone heterogeneity for RNA [54] or mixed nucleotide backbones formed from RNA, DNA or other nucleic acid types [55]) have fascinating properties. In particular, some chimeric backbones decrease duplex stabilities, which could help to mitigate the strand dissociation problem [56].…”

Modified nucleic acids: replication, evolution, and next-generation therapeutics

“…An interesting development in this context is the discovery that mixed backbone chemistries can display novel emergent properties. For example, Krishnamurthy and colleagues probed the ability of XNA-RNA chimeric oligonucleotides to hybridize with their natural nucleic acid counterparts and found that the otherwise non-pairing ribuloNA can be interspersed with RNA or DNA building blocks to yield oligonucleotides with comparable or higher duplex thermal stability than natural systems and tuneable base-pairing properties [ 26 ]. The authors suggest that such a system could be used to mimic natural base-pairing rules with a reduced number of bases, storing information in the sugar in place of the GC base pair.…”

Efficient synthesis and replication of diverse sequence libraries composed of biostable nucleic acid analogues

“… 19 , 21 , 25 and 48 ) offer a means to navigate a greater variety of chemical and structural space, potentially enabling discovery and evolution of more diverse functional 3D motifs and properties made possible by interactions between alternative polymer chemistries. 49 Here, we expand the range of mixed-chemistry synthetic genetic systems using two XNA polymerase blends to efficiently synthesise and reverse transcribe mixtures of LNA and/or 2′OMe-RNA.…”