Tautomeric Equilibria of Nucleobases in the Hachimoji Expanded Genetic Alphabet
Eberlein L, Beierlein F, van Eikema Hommes N, Radadiya A, Heil J, Benner SA, Clark T, Kast SM, Richards NG (2020)
Publication Type: Journal article
Publication year: 2020
Journal
Book Volume: 16
Pages Range: 2766-2777
Journal Issue: 4
Abstract
Evolution has yielded biopolymers that are constructed from exactly four building blocks and are able to support Darwinian evolution. Synthetic biology aims to extend this alphabet, and we recently showed that 8-letter (hachimoji) DNA can support rule-based information encoding. One source of replicative error in non-natural DNA-like systems, however, is the occurrence of alternative tautomeric forms, which pair differently. Unfortunately, little is known about how structural modifications impact free-energy differences between tautomers of the non-natural nucleobases used in the hachimoji expanded genetic alphabet. Determining experimental tautomer ratios is technically difficult, and so, strategies for improving hachimoji DNA replication efficiency will benefit from accurate computational predictions of equilibrium tautomeric ratios. We now report that high-level quantum-chemical calculations in aqueous solution by the embedded cluster reference interaction site model, benchmarked against free-energy molecular simulations for solvation thermodynamics, provide useful quantitative information on the tautomer ratios of both Watson-Crick and hachimoji nucleobases. In agreement with previous computational studies, all four Watson-Crick nucleobases adopt essentially only one tautomer in water. This is not the case, however, for non-natural nucleobases and their analogues. For example, although the enols of isoguanine and a series of related purines are not populated in water, these heterocycles possess N1-H and N3-H keto tautomers that are similar in energy, thereby adversely impacting accurate nucleobase pairing. These robust computational strategies offer a firm basis for improving experimental measurements of tautomeric ratios, which are currently limited to studying molecules that exist only as two tautomers in solution.
Authors with CRIS profile
Frank Beierlein
Computer-Chemie-Centrum
Nicolaas van Eikema Hommes
Computer-Chemie-Centrum
Timothy Clark
Computer-Chemie-Centrum
Involved external institutions
Technische Universität Dortmund
Germany (DE)
Cardiff University
United Kingdom (GB)
Foundation for Applied Molecular Evolution (FfAME)
United States (USA) (US)
Germany (DE)
Cardiff University
United Kingdom (GB)
Foundation for Applied Molecular Evolution (FfAME)
United States (USA) (US)
How to cite
APA:
Eberlein, L., Beierlein, F., van Eikema Hommes, N., Radadiya, A., Heil, J., Benner, S.A.,... Richards, N.G. (2020). Tautomeric Equilibria of Nucleobases in the Hachimoji Expanded Genetic Alphabet. Journal of Chemical Theory and Computation, 16(4), 2766-2777. https://dx.doi.org/10.1021/acs.jctc.9b01079
MLA:
Eberlein, Lukas, et al. "Tautomeric Equilibria of Nucleobases in the Hachimoji Expanded Genetic Alphabet." Journal of Chemical Theory and Computation 16.4 (2020): 2766-2777.
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