Role of Pseudoisocytidine Tautomerization in Triplex-Forming Oligonucleotides: In Silico and in Vitro Studies

ACS Omega
Yossa Dwi HartonoAlessandra Villa

Abstract

Pseudoisocytidine (ΨC) is a synthetic cytidine analogue that can target DNA duplex to form parallel triplex at neutral pH. Pseudoisocytidine has mainly two tautomers, of which only one is favorable for triplex formation. In this study, we investigated the effect of sequence on ΨC tautomerization using λ-dynamics simulation, which takes into account transitions between states. We also performed in vitro binding experiments with sequences containing ΨC and furthermore characterized the structure of the formed triplex using molecular dynamics simulation. We found that the neighboring methylated or protonated cytidine promotes the formation of the favorable tautomer, whereas the neighboring thymine or locked nucleic acid has a poor effect, and consecutive ΨC has a negative influence. The deleterious effect of consecutive ΨC in a triplex formation was confirmed using in vitro binding experiments. Our findings contribute to improving the design of ΨC-containing triplex-forming oligonucleotides directed to target G-rich DNA sequences.

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Methods Mentioned

BETA
nuclear magnetic resonance
NMR
Assay
electrophoresis

Software Mentioned

CHARMM BLOCK
OpenMM
3DNA
Quantity One
CHARMM

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