Replacing Thymine with a Strongly Pairing Fifth Base: a Combined Quantum Mechanics and Molecular Dynamics Study
Name:
Replacing thymine-1-s2.0-S200103702100057X-main.pdf
Size:
3.021Mb
Format:
PDF
Description:
Accepted Article
Type
ArticleKAUST Department
Biological and Environmental Science and Engineering (BESE) DivisionChemical Science Program
KAUST Catalysis Center (KCC)
Physical Science and Engineering (PSE) Division
Date
2021-02-23Online Publication Date
2021-02-23Print Publication Date
2021Embargo End Date
2022-02-23Submitted Date
2020-12-04Permanent link to this record
http://hdl.handle.net/10754/667656
Metadata
Show full item recordAbstract
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.Citation
Chawla, M., Gorle, S., Rajjak Shaikh, A., Oliva, R., & Cavallo, L. (2021). Replacing Thymine with a Strongly Pairing Fifth Base: a Combined Quantum Mechanics and Molecular Dynamics Study. Computational and Structural Biotechnology Journal. doi:10.1016/j.csbj.2021.02.006Sponsors
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.Publisher
Elsevier BVAdditional Links
https://linkinghub.elsevier.com/retrieve/pii/S200103702100057Xae974a485f413a2113503eed53cd6c53
10.1016/j.csbj.2021.02.006