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Cyano Modification on Uridine Decreases Base‐Pairing Stability and Specificity through Neighboring Disruption in RNA Duplex
Author(s) -
Mao Song,
Ranganathan Srivathsan V.,
Tsai HsuChun,
Haruehanroengra Phensinee,
Shen Fusheng,
Valsangkar Vibhav A.,
Han Bo,
Hassan Abdalla E. A.,
Chen Alan,
Sheng Jia
Publication year - 2018
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201800399
Subject(s) - duplex (building) , base pair , pairing , rna , uridine , oligonucleotide , chemistry , nucleotide , stereochemistry , transfer rna , context (archaeology) , crystallography , biology , biochemistry , dna , physics , gene , quantum mechanics , paleontology , superconductivity
5‐Cyanomethyluridine (cnm 5 U) and 5‐cyanouridine (cn 5 U), the two uridine analogues, were synthesized and incorporated into RNA oligonucleotides. Base‐pairing stability and specificity studies in RNA duplexes indicated that cnm 5 U slightly decreased the stability of the duplex but retained the base‐pairing preference. In contrast, cn 5 U dramatically decreased both base‐pairing stability and specificity between U:A and other noncanonical U:G, U:U, and U:C pairs. In addition, the cn 5 U:G pair was found to be stronger than the cn 5 U:A pair and the other mismatched pairs in the context of a RNA duplex; this implied that cn 5 U might slightly prefer to recognize G over A. Our mechanistic studies by molecular simulations showed that the cn 5 U modification did not directly affect the base pairing of the parent nucleotide; instead, it weakened the neighboring base pair in the 5′ side of the modification in the RNA duplexes. Consistent with the simulation data, replacing the Watson–Crick A:U pair to a mismatched C:U pair in the 5′‐neighboring site did not affect the overall stability of the duplex. Our work reveals the significance of the electron‐withdrawing cyano group in natural tRNA systems and provides two novel building blocks for constructing RNA‐based therapeutics.