Replacing Thymine with a Strongly Pairing Fifth Base: a Combined Quantum Mechanics and Molecular Dynamics Study

Mohit Chawla, Suresh Gorle, Abdul Rajjak Shaikh, Romina Oliva, Luigi Cavallo

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13 Scopus citations


The non-natural ethynylmethylpyridone C-nucleoside (W), a thymidine (T) analogue that can be incorporated in oligonucleotides by automated synthesis, has recently been reported to form a high fidelity base pair with adenosine (A) and to be well accommodated in B-DNA duplexes. The enhanced binding affinity for A of W, as compared to T, makes it an ideal modification for biotechnological applications, such as efficient probe hybridization for the parallel detection of multiple DNA strands. In order to complement the experimental study and rationalize the impact of the non-natural W nucleoside on the structure, stability and dynamics of DNA structures, we performed quantum mechanics (QM) calculations along with molecular dynamics (MD) simulations. Consistently with the experimental study, our QM calculations show that the A:W base pair has an increased stability as compared to the natural A:T pair, due to an additional CH-π interaction. Furthermore, we show that mispairing between W and guanine (G) causes a distortion in the planarity of the base pair, thus explaining the destabilization of DNA duplexes featuring a G:W pair. MD simulations show that incorporation of single or multiple consecutive A:W pairs in DNA duplexes causes minor changes to the intra- and inter-base geometrical parameters, while a moderate widening/shrinking of the major/minor groove of the duplexes is observed. QM calculations applied to selected stacks from the MD simulations also show an increased stacking energy for W, over T, with the neighboring bases.
Original languageEnglish (US)
JournalComputational and Structural Biotechnology Journal
StatePublished - Feb 23 2021

Bibliographical note

KAUST Repository Item: Exported on 2021-02-25
Acknowledgements: L.C. and M. C. acknowledges King Abdullah University of Science and Technology (KAUST) for support and the KAUST Supercomputing Laboratory for providing computational resources of the supercomputer Shaheen II. R.O. thanks MIUR-FFABR (Fondo per il Finanziamento Attività Base di Ricerca) for funding.


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