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SUMMARY:Quantum tunnelling effects in the guanine-thymine wobble misincorp
 oration via tautomerism - Louie Slocombe\, Quantum Biology Doctoral Traini
 ng Centre\, University of Surrey
DTSTART:20230126T150000Z
DTEND:20230126T160000Z
UID:TALK196342@talks.cam.ac.uk
CONTACT:Stephen Walley
DESCRIPTION:DNA polymerase is an enzyme that catalyzes the synthesis of DN
 A molecules by matching complementary deoxyribonucleoside triphosphates (d
 NTP) to the template DNA strand using the standard Watson–Crick base pai
 r rules. However\, when a noncomplementary dNTP diffuses into the active s
 ite during the polymerase dNTP sampling\, the polymerase domain will trans
 ition from an open to an ajar conformation\, thus forming a different nons
 tandard hydrogen-bonded base-pairing arrangement called wobble mispair [1]
 . While there are other sources of replication errors\, the fidelity of re
 plication primarily depends on the ability of polymerases to select and in
 corporate the correct complementary base [2].\n\nConsequently\, misincorpo
 rating a noncomplementary DNA base in the polymerase active site is a crit
 ical source of replication errors that can lead to genetic mutations [3]. 
 In this work [4]\, we model the mechanism of wobble mispairing and the sub
 sequent rate of misincorporation errors by coupling first-principles quant
 um chemistry calculations to an open quantum systems master equation [5]. 
 This methodology allows us to accurately calculate the proton transfer bet
 ween bases\, allowing the misincorporation and formation of mutagenic taut
 omeric forms of DNA bases. Our calculated rates of genetic error formation
  are in excellent agreement with experimental observations in DNA. Further
 more\, our quantum mechanics/molecular mechanics model predicts the existe
 nce 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 fr
 equency of the polymerase.\n\nReferences\n\n[1] Wang\, W.\, Hellinga\, H. 
 W.\, & Beese\, L. S. (2011). Proceedings of the National Academy of Scienc
 es\, 108(43)\, 17644-17648.\n\n[2] Kimsey\, I. J.\, Szymanski\, E. S.\, Za
 hurancik\, W. J.\, Shakya\, A.\, Xue\, Y.\, Chu\, C. C.\, ... & Al-Hashimi
 \, H. M. (2018). Nature\, 554(7691)\, 195-201.\n\n[3] Li\, P.\, Rangadurai
 \, A.\, Al-Hashimi\, H. M.\, & Hammes-Schiffer\, S. (2020). Journal of the
  American Chemical Society\, 142(25)\, 11183-11191.\n\n[4] Slocombe\, L.\,
  Winokan\, M.\, Al-Khalili\, J.\, & Sacchi\, M. (2022). The Journal of Phy
 sical Chemistry Letters\, 14\, 9-15.\n\n[5] Slocombe\, L.\, Sacchi\, M.\, 
 & Al-Khalili\, J. (2022). Communications Physics\, 5(1)\, 1-9.\n
LOCATION:Mott Seminar Room\, Cavendish Laboratory
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