Multiscale Investigation On The Role Of Quantum Effects In Photoinduced Mechanisms Of DNA Repair

The cyclobutane pyrimidine dimer (T=T dimer) is a DNA mutation made when two adjacent thymine bases bond together after UV radiation damage. If the DNA is not repaired, the dimer will be deadly for the cell and is the leading cause of melanoma in humans. The dimer can be broken, and the DNA repaired when a single electron is donated to the dimer from an enzyme or surrounding nucleotide. Cyclic exchange of this electron will break the dimer, and afterwards it is returned to the donor.

Experimental evidence [1] suggests that, for the DNA sequence: G-A-T=T, absorption of UVB/UVC light will result its ionisation, and its reduction of adenine, as it passes the electron to it. In turn adenine will reduce the dimer, leading to its repair process and the subsequent return of the electron to guanine. I plan to produce a computational model of this sequence of events, to provide a better understanding of the nature and feasibility of this reaction.

I will use a technique known as QM/MM modelling- using QM codes, that account for quantum mechanical effects, only in the reactive site and for all other parts of the model: MM codes, that only model larger scale molecular mechanics. This allows for a model that is both very accurate and large enough to be biologically realistic.

I will also produce a QM/MM model to look at the use of quantum mechanics in the active site of the enzyme photolyase during dimer repair. There are many unanswered questions about the dominance of different electron transfer mechanisms from the active site to the dimer across photolyase enzyme species and environmental situations.