Abstract
DNA mutation occurring in the absence of external factors remains an open problem. Watson and Crick’s pioneering work on DNA structure suggested that rare protonation states of DNA bases could be a source of such spontaneous mutations. Löwdin proposed quantum tunnelling as a source of tautomeric A*T* and G*C* nucleotide pairs. During replication, such tautomeric pairs can form mismatches (A*C, GT*, AC*, and G*T) that evade error correction mechanisms by mimicking the structure of canonical DNA. Existing computational models of DNA tautomerism have often oversimplified the dynamical aspects of replication enzymes and their biological microenvironment. This thesis extends established methods to provide a comprehensive description of the quantum phenomenon of proton transfer in DNA. The effect of mechanical separation forces on the behaviour of AT and GC base pairs serves as a model of strand separation conditions induced by a helicase enzyme. The results from complementary quantum mechanical (QM) and molecular mechanics (MM) models reveal that tautomeric populations can be trapped despite their (sub-picosecond) lifetimes, challenging previous assumptions which dismiss their relevance to mutations. The effect of a more realistic replication environment on proton transfer within DNA is explored. Multiscale QM/MM models allow for the determination of the free energy surface experienced by protons in both aqueous DNA and in complex with an explicit helicase enzyme. The results highlight that PcrA helicase reduces the stability of G∗C∗, potentially due to a natural selection pressure to reduce spontaneous mutations. Equilibrium descriptions of the proton transfer obtained from umbrella sampling were complemented with an instantaneous approach where the proton can be isolated from other atomic motions, leading to a novel time-dependent potential for the proton transfer. An alternative mechanism for spontaneous mutations is considered, involving proton transfer within a polymerase enzyme during DNA synthesis. Dynamical QM/MM simulations suggest that the polymerase’s dynamics could prime a GT wobble mismatch into a tunnelling-ready state resulting in a heightened rate of mismatches. Finally, the role of tautomers in genetic disorders is contextualised, and the limitations of existing theoretical descriptions are acknowledged. The potential for future research, including investigating quantum effects in DNA methylation, gene expression, and epigenetics is outlined.