Decoding Stability and Selectivity in Unnatural DNA Base Pairs with Spatially Separated Recognition Interfaces.
- 1Departament de Química Inorgànica i Orgànica & IQTCUB, Universitat de Barcelona, Martí i Franquès 1-11, 08028Barcelona, Spain.
- 2ICREA, Passeig Lluís Companys 23, 08010Barcelona, Spain.
Abstract
Unnatural base pairs (UBPs) with spatially separated recognition interfaces offer a promising route to expand the genetic alphabet, yet the origin of their enhanced stability remains unclear. Herein, we present a quantum chemical investigation of alkynylated purine-pyridazine UBPs, combining Kohn-Sham molecular orbital and energy decomposition analyses to characterize both base-pairing and π-π stacking interactions. The UBPs display slightly stronger base-pair interaction energies than the canonical G-C pair, arising from a favorable balance of electrostatic and dispersion interactions that compensate for the increased Pauli repulsion. Importantly, modeling of experimentally relevant DNA trimers reveals a quite good correlation between increasing UBP content, enhanced stacking interaction energies, and experimentally observed increases in melting temperature. This agreement highlights the central role of dispersion-driven stabilization and supports the reliability of the computational approach in reproducing the observed trends. These results provide key insights into the factors governing UBP stability and establish a foundation for the rational design of expanded genetic systems.
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BibTeX
@article{bermejo2026decoding,
title = {{Decoding Stability and Selectivity in Unnatural DNA Base Pairs with Spatially Separated Recognition Interfaces.}},
author = {Andreu Bermejo and Josep Maria Bofill and Jordi Poater},
journal = {The Journal of organic chemistry},
year = {2026},
month = sep,
doi = {10.1021/acs.joc.6c01057},
url = {https://europepmc.org/article/MED/42917102},
note = {CC BY},
}
RIS
TY - JOUR
TI - Decoding Stability and Selectivity in Unnatural DNA Base Pairs with Spatially Separated Recognition Interfaces.
AU - Andreu Bermejo
AU - Josep Maria Bofill
AU - Jordi Poater
PY - 2026
DA - 2026/09/01
JO - The Journal of organic chemistry
DO - 10.1021/acs.joc.6c01057
UR - https://europepmc.org/article/MED/42917102
AB - Unnatural base pairs (UBPs) with spatially separated recognition interfaces offer a promising route to expand the genetic alphabet, yet the origin of their enhanced stability remains unclear. Herein, we present a quantum chemical investigation of alkynylated purine-pyridazine UBPs, combining Kohn-Sham molecular orbital and energy decomposition analyses to characterize both base-pairing and π-π stacking interactions. The UBPs display slightly stronger base-pair interaction energies than the canonical G-C pair, arising from a favorable balance of electrostatic and dispersion interactions that compensate for the increased Pauli repulsion. Importantly, modeling of experimentally relevant DNA trimers reveals a quite good correlation between increasing UBP content, enhanced stacking interaction energies, and experimentally observed increases in melting temperature. This agreement highlights the central role of dispersion-driven stabilization and supports the reliability of the computational approach in reproducing the observed trends. These results provide key insights into the factors governing UBP stability and establish a foundation for the rational design of expanded genetic systems.
SN - 0022-3263
SN - 1520-6904
ER -