Intrastrand backbone-nucleobase interactions stabilize unwound right-handed helical structures of heteroduplexes of L-aTNA/RNA and SNA/RNA

Yukiko Kamiya,Tatsuya Suzuki,Atsuji Kodama,Susumu Uchiyama,Keiji Murayama,Koichi Kato,Hiromu Kashida,Tadashi Satoh,Hiroyuki Asanuma

doi:10.1038/s42004-020-00400-2

Abstract

Xeno nucleic acids, which are synthetic analogues of natural nucleic acids, have potential for use in nucleic acid drugs and as orthogonal genetic biopolymers and prebiotic precursors. Although few acyclic nucleic acids can stably bind to RNA and DNA, serinol nucleic acid (SNA) and L-threoninol nucleic acid (L-aTNA) stably bind to them. Here we disclose crystal structures of RNA hybridizing with SNA and with L-aTNA. The heteroduplexes show unwound right-handed helical structures. Unlike canonical A-type duplexes, the base pairs in the heteroduplexes align perpendicularly to the helical axes, and consequently helical pitches are large. The unwound helical structures originate from interactions between nucleobases and neighbouring backbones of L-aTNA and SNA through CH–O bonds. In addition, SNA and L-aTNA form a triplex structure via C:G*G parallel Hoogsteen interactions with RNA. The unique structural features of the RNA-recognizing mode of L-aTNA and SNA should prove useful in nanotechnology, biotechnology, and basic research into prebiotic chemistry.

Highlights

Xeno nucleic acids, which are synthetic analogues of natural nucleic acids, have potential for use in nucleic acid drugs and as orthogonal genetic biopolymers and prebiotic precursors
The duplexes formed by an L-aTNA strand LT8a (3′-GCAGCAGC-1′) with an RNA strand R8Br (5′-GCUGC-BrU-GC-3′) and an serinol nucleic acid (SNA) strand S8a ((S)-GCAGCAGC-(R)) with the R8Br were prepared
The L-aTNA/RNA crystal diffracted at 1.5-Å resolution and the SNA/RNA crystal diffracted at 1.7-Å resolution

Summary

Introduction

Xeno nucleic acids, which are synthetic analogues of natural nucleic acids, have potential for use in nucleic acid drugs and as orthogonal genetic biopolymers and prebiotic precursors. Xeno nucleic acids (XNAs) are synthetic analogues that retain natural nucleobases but are replaced with backbone structures different from DNA and RNA They have potential for use in nucleic acid-based drugs, in development of artificial genetic polymers, and in the prebiotic field[1,2,3,4,5,6,7,8]. We recently discovered acyclic nucleic acids serinol nucleic acid (SNA) and L-threoninol nucleic acid (L-aTNA) can form stable duplexes with RNA in a sequence-specific manner[33,34,35] Since they are structurally simple, readily synthesized, excellent water solubility, and high nucleases resistance, various applications have been realized based on hybridization with RNA such as a high-sensitive molecular beacon and nucleic acid-based drug candidates, including siRNAs, anti-miRNA oligonucleotides, and exon-skipping type antisense oligonucleotides[36,37,38,39,40,41,42,43]. L-aTNA/RNA and SNA/RNA form righthanded helical structures with large helical pitch involving Watson–Crick base pairs and parallel-type Hoogsteen base pairs

Methods

Results

Conclusion