Fatma ÇiçekY., Sema YöşiliE.
The genetic stability of DNA is one of the most important topics in molecular biology. Proton transfer along the hydrogen bonds of DNA can lead to tautomerization and thus, point mutations that pose a threat to the genetic stability of DNA. Slocombe et al., have presented a theoretical analysis of the hydrogen bonds between the Guanine – Cytosine (G – C) nucleotide pair. This theoretical analysis sought to accurately model the effect of the structure of bp, hydrogen bonding proton, quantum dynamics and energy-consuming cellular environment. Because of the importance of quantum tunnelling at biological temperatures. Slocombe et al., have found that the tautomeric forms of G – C interconvert in a far shorter timer compared to the biological forms. Therefore, as opposed to thermal equilibrium was quickly reached.
It has been suggested by Watson and Crick in their seminal paper that tautomerization of DNA base pairs can cause stable errors in the genome. Their proposal for the mechanism was double proton transfer across hydrogen bonds within the G – C or Adenine – Thymine (A – T) base pairs. This mechanism has been of particular interest due to the possible relation between quantum tunnelling of protons and separation of the two strands of DNA.
H – bond protons transfer from one base site on one strand to the corresponding site on the other strand causing a conversion of the standard canonical form to its tautomeric form. To see that the tautomeric form of the base is incompatible with the mismatched base in the complementary sequence, then each strand could go through the DNA replication complex if this tautomeric pair were surviving the DNA fragmentation process led by helicase (an enzyme that helps to separate DNA strands). Moreover, this mismatched pair can avoid the replisome checkpoints by adopting a similar structure to the Watson and Crick base pair. This results in a faulty mismatch and thus a point mutation.
Slocombe et al., have shown that the double proton transfer process occurs very rapidly and the lifetimes of tautomeric states do not play a significant role in determining the probability of a base pair mismatch. On the other hand, a chemical balance; is defined as the ratio of base pairs in two different forms. The chemical balance, Keq, has been generally written as Keq=[G*–C*]/[G–C], which has been the ratio between the concentration of products (tautomeric pair) and reactants (canonical pair) present at chemical equilibrium. However, the concentrations have been modified by a quantum activity coefficient, Γqm, needs to have been included as a factor such that Keq-qm = Γqm × [G*–C*]/[G–C].
For G–C tautomerism, Keq was easily obtained from the difference in Gibbs free energy between products and reactants, ΔG, Keq= exp(ΔG/kbT) and was calculated by ab initio methods or measured experimentally. However, without an accurate estimation of the activity coefficient, Slocombe et al., did not determine the amount of interest [G*–C*]/[G–C]. Instead, they performed a purely quantum mechanical calculation to derive the probability of G*–C* occupation within an open quantum system (OQS) approach.
Recently, some application methods have been developed to investigate the tautomerization of A–T and G–C base pairs. In one of these application methods, the proton displacement process; It has been suggested that, together with the strength of hydrogen bonds in DNA base pairs, it causes several substances to follow an anomalous temperature dependence due to their fine balance. The problem with such approaches is that while proton dynamics are handled quantum mechanically, the connection between them and the surrounding environment is handled through approximate “classical” thermostats. Incompatibility and dispersion have not been properly addressed in adiabatic thermally uncoupled tunnelling models. Therefore, Slocombe et al., used purely OQS treatment of the dynamics of proton transfer and subsequent populations in the G-C tautomerization reaction.
Slocombe et al., investigated the proton transfer mechanism in the H-bonds of the G-C base pair in an OQS model. In this approach, the quantum system (H-bond proton at the Double-well potential) has undergone disintegration and decoherence due to binding to a surrounding heat bath (cellular environment). The environment also acted as a source of thermal activation, stimulating the proton to higher energy states, and promoting tunnelling into the right-hand tautomeric state. At t→∞, the thermal equilibrium distribution was four orders of magnitude larger for the proton to be in tautomeric form than predicted by classical and semi-classical studies previously reported for it.
Slocombe et al., also want to emphasize that adding more dimensions to the Hamiltonian system can lead to potential corner-cutting effects that can further increase speed. Furthermore, the forward and reverse proton transfer processes were significantly faster than the helical fission timescale. Although experimental measurements of tautomerization rates for the G–C double proton transfer reaction are still not available, Slocombe et al., hoped that their theoretical results would prompt new experimental measurements of the proton transfer reaction that should make them fundamentally rethink our understanding of the possibility of point mutations in DNA.
Reference
Slocombe, L., Sacchi, M., & Al-Khalili, J. (2022). An open quantum systems approach to proton tunnelling in DNA. Communications Physics, 5(1), 109. https://doi.org/10.1038/s42005-022-00881-8
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