Non-natural (synthetic) modifications can be introduced in nucleic acid structures for targeted applications. For instance, fluorescent modified nucleobases can be used as labeling tags to study the interaction of nucleic acids with other biomolecules. In this context, a fluorescent ribonucleoside alphabet consisting of highly emissive purine (tzA, tzG) and pyrimidine (tzU, tzC) analogues, all derived from the isothiazolo[4,3-d]pyrimidine heterocycle, has been synthetized and experimentally characterized (1). Here in, we present a theoretical characterization of the above fluorescent non-natural nucleobases (2) based on accurate electronic structure calculations (3,4). Our modeling shows that the non-natural bases have minimal impact on the structure and stability of the classical Watson–Crick base pairs, thus mimicking H-bonding of natural bases in RNA duplexes. Conversely, our calculations indicate that H-bonded base pairs involving the Hoogsteen edge are destabilized relatively to their natural counterparts. Analysis of the photophysical properties of the non-natural bases allowed us to correlate their absorption/emission peaks to the strong impact of the modification on the energy of the lowest unoccupied molecular orbital, LUMO, which is stabilized by roughly 1.0–1.2 eV relatively to the natural analogues, while the highest occupied molecular orbital, HOMO, is not substantially affected. As a result, the HOMO–LUMO gap is reduced from 5.3–5.5 eV in the natural bases to 4.0–4.4 eV in the modified ones, with a consequent bathochromic shift in the absorption and emission spectra.

Structural and energetic characterization of the emissive RNA alphabet based on the isothiazolo[4,3-d]pyrimidine heterocycle core

253rd National Meeting (2017)

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