Quantum and classical effects in DNA point mutations: Watson–Crick tautomerism in AT and GC base pairs

Slocombe, Louie; Al-Khalili, Jim; Sacchi, Marco

doi:10.1039/d0cp05781a

Cited by 38 publications

(55 citation statements)

References 54 publications

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Section: Discussionmentioning

confidence: 93%

“…On the other hand, computational studies suggest that the monomeric form of the tautomers are stable and extremely long-lived due to their prohibitively large reaction barriers [4,13,36,37]. Based on previous evaluations [4] of tunnelling in this system, we expect that the tautomeric population of the monomeric forms are un-likely to see any meaningful change while in transit from the helicase until it matches another base pair. Consequently, any last line of defence against the tautomer's uptake would take place during the exonuclease proofreading process during which slight modifications to the DNA structure caused by the tautomeric mismatch could be corrected.…”

Section: Discussionmentioning

confidence: 93%

“…The proposed mechanism for such tautomerisation is double proton transfer along the hydrogen bonds within base pairs, G-C or A-T [2,3]. This mechanism is of particular interest due to what has been predicted to be a significant contribution from the quantum tunnelling of the protons through a potential barrier separating the nucleotide base pairs on the two strands of DNA [4]. The mechanism has been widely studied theoretically [4][5][6][7] and, more rarely, experimentally [8,9].…”

mentioning

confidence: 99%

“…Therefore, we employ in this work a fully open quantum system treatment of the proton transfer mechanism to model the G-C tautomerisation. Our decision to study G-C rather than A-T is because the tautomeric state, A*-T*, is extremely unstable, with a fleetingly short lifetime, and therefore not as likely to play a role in mutagenesis [4,5,7,13].…”

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confidence: 99%

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An Open Quantum Systems approach to proton tunnelling in DNA

Slocombe¹,

Sacchi²,

Al-Khalili³

2021

Preprint

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One of the most important topics in molecular biology is the genetic stability of DNA. One threat to this stability is proton transfer along the hydrogen bonds of DNA that could lead to tautomerisation, hence creating point mutations. We present a theoretical analysis of the hydrogen bonds between the Guanine-Cytosine (G-C) nucleotide, which includes an accurate model of the structure of the base pairs, the quantum dynamics of the hydrogen bond proton, and the influence of the decoherent and dissipative cellular environment. We determine that the quantum tunnelling contribution to the process is several orders of magnitude larger than the contribution from classical over-the-barrier hopping. Due to this significant quantum contribution, we find that the canonical and tautomeric forms of G-C inter-convert over timescales far shorter than biological ones and hence thermal equilibrium is rapidly reached. Furthermore, we find a large tautomeric occupation probability of 1.73 × 10 −4 , suggesting that such proton transfer may well play a far more important role in DNA mutation than has hitherto been suggested. Our results could have far-reaching consequences for current models of genetic mutations.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 93%

mentioning

confidence: 99%

mentioning

confidence: 99%

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An Open Quantum Systems approach to proton tunnelling in DNA

Slocombe¹,

Sacchi²,

Al-Khalili³

2021

Preprint

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“…(B) Structural evidence for the stabilization of A-C base pair in W-C conformation, almost indistinguishable from the A-T base pair in active site of a high fidelity DNA polymerase. Figure is adapted from reference ( Wang et al, 2011 ; Slocombe et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Structural Insights Into Tautomeric Dynamics in Nucleic Acids and in Antiviral Nucleoside Analogs

Fedeles

Singh

2022

Front. Mol. Biosci.

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DNA (2′-deoxyribonucleic acid) and RNA (ribonucleic acid) play diverse functional roles in biology and disease. Despite being comprised primarily of only four cognate nucleobases, nucleic acids can adopt complex three-dimensional structures, and RNA in particular, can catalyze biochemical reactions to regulate a wide variety of biological processes. Such chemical versatility is due in part to the phenomenon of nucleobase tautomerism, whereby the bases can adopt multiple, yet distinct isomeric forms, known as tautomers. For nucleobases, tautomers refer to structural isomers that differ from one another by the position of protons. By altering the position of protons on nucleobases, many of which play critical roles for hydrogen bonding and base pairing interactions, tautomerism has profound effects on the biochemical processes involving nucleic acids. For example, the transient formation of minor tautomers during replication could generate spontaneous mutations. These mutations could arise from the stabilization of mismatches, in the active site of polymerases, in conformations involving minor tautomers that are indistinguishable from canonical base pairs. In this review, we discuss the evidence for tautomerism in DNA, and its consequences to the fidelity of DNA replication. Also reviewed are RNA systems, such as the riboswitches and self-cleaving ribozymes, in which tautomerism plays a functional role in ligand recognition and catalysis, respectively. We also discuss tautomeric nucleoside analogs that are efficacious as antiviral drug candidates such as molnupiravir for coronaviruses and KP1212 for HIV. The antiviral efficacy of these analogs is due, in part, to their ability to exist in multiple tautomeric forms and induce mutations in the replicating viral genomes. From a technical standpoint, minor tautomers of nucleobases are challenging to identify directly because they are rare and interconvert on a fast, millisecond to nanosecond, time scale. Nevertheless, many approaches including biochemical, structural, computational and spectroscopic methods have been developed to study tautomeric dynamics in RNA and DNA systems, and in antiviral nucleoside analogs. An overview of these methods and their applications is included here.

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Atomistic mechanisms of the tautomerization of the G·C base pairs through the proton transfer: quantum-chemical survey

2021

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This study is devoted to the investigation of the G•C* t O2 (WC)↔G* NH3 •C* t (WC), G•C* O2 (WC)↔G* NH3 •C* (WC) and G*•C* O2 (WC)↔G* NH3 •C(w WC ) ↓ tautomerization reactions occurring through the proton transfer, obtained at the MP2/6-311++G(2df,pd)//B3LYP/6-311++G(d,p) level of theory in gas phase under normal conditions (T=298.15 K). These reactions lead to the formation of the G* NH3 •C* t (WC), G* NH3 •C*(WC) and G* NH3 •C(w WC ) ↓ base pairs by the participation of the G* NH3 base with NH 3 group. Gibbs free energies of activation for these reactions are 6.43, 11.00 and 1.63 kcal•mol -1 , respectively. All of these tautomerization reactions are dipole active. Finally, we believe that these non-dissociative processes, which are tightly connected with the tautomeric transformations of the G•C base pairs, play outstanding role in the supporting of the spatial structure of the DNA and RNA molecules with various functional purposes.

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Quantum and classical effects in DNA point mutations: Watson–Crick tautomerism in AT and GC base pairs

Abstract: Proton transfer along the hydrogen bonds of DNA can lead to the creation of short-lived, but biologically relevant point mutations that can further lead to gene mutation and, potentially, cancer.

Cited by 38 publications

References 54 publications

An Open Quantum Systems approach to proton tunnelling in DNA

An Open Quantum Systems approach to proton tunnelling in DNA

Structural Insights Into Tautomeric Dynamics in Nucleic Acids and in Antiviral Nucleoside Analogs

Atomistic mechanisms of the tautomerization of the G·C base pairs through the proton transfer: quantum-chemical survey

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