Abstract

DNA polymerase is an enzyme that catalyzes the synthesis of DNA molecules by matching complementary deoxyribonucleoside triphosphates (dNTP) to the template DNA strand using the standard Watson–Crick base pair rules. However, when a noncomplementary dNTP diffuses into the active site during the polymerase dNTP sampling, the polymerase domain will transition from an open to an ajar conformation, thus forming a different nonstandard hydrogen-bonded base-pairing arrangement called wobble mispair [1]. While there are other sources of replication errors, the fidelity of replication primarily depends on the ability of polymerases to select and incorporate the correct complementary base [2].

Consequently, misincorporating a noncomplementary DNA base in the polymerase active site is a critical source of replication errors that can lead to genetic mutations [3]. In this work [4], we model the mechanism of wobble mispairing and the subsequent rate of misincorporation errors by coupling first-principles quantum chemistry calculations to an open quantum systems master equation [5]. This methodology allows us to accurately calculate the proton transfer between bases, allowing the misincorporation and formation of mutagenic tautomeric forms of DNA bases. Our calculated rates of genetic error formation are in excellent agreement with experimental observations in DNA . Furthermore, our quantum mechanics/molecular mechanics model predicts the existence of a short-lived “tunnelling-ready” configuration along the wobble reaction pathway in the polymerase active site, dramatically increasing the rate of proton transfer by a hundredfold, demonstrating that quantum tunnelling plays a critical role in determining the transcription error frequency of the polymerase.

References

[1] Wang, W., Hellinga, H. W., & Beese, L. S. (2011). Proceedings of the National Academy of Sciences, 108(43), 17644-17648.

[2] Kimsey, I. J., Szymanski, E. S., Zahurancik, W. J., Shakya, A., Xue, Y., Chu, C. C., ... & Al-Hashimi, H. M. (2018). Nature, 554(7691), 195-201.

[3] Li, P., Rangadurai, A., Al-Hashimi, H. M., & Hammes-Schiffer, S. (2020). Journal of the American Chemical Society, 142(25), 11183-11191.

[4] Slocombe, L., Winokan, M., Al-Khalili, J., & Sacchi, M. (2022). The Journal of Physical Chemistry Letters, 14, 9-15.

[5] Slocombe, L., Sacchi, M., & Al-Khalili, J. (2022). Communications Physics, 5(1), 1-9.