Conformational Dynamics of 8-Oxoguanine Mispairing Reveal a Mechanism of Polymerase {\lambda} Misincorporation

Experimental evidence has shown the stability of oxygen-stress-damaged guanine, known as 8-oxoguanine.

This common oxygen-damaged nucleobase is often found in the presence of reactive oxygen species and can result in the mispairing between adenine and 8-oxoguanine in a Hoogsteen pair.

We have computationally investigated the role of 8-oxoguanine to support experimental results and focus the investigation towards the polymerase structure, identifying how 8-oxoguanine interacts in the polymerase environment.

Quantum mechanical investigations show the Hoogsteen pairing of adenine and 8-oxoguanine is the most energetically favourable state compared to a Watson-Crick state, supporting experimental evidence.

Molecular Dynamical calculation of 8-oxoguanine located in B-DNA provide an average C1' backbone spacing of 1.1 nm compared to adenine-thymine spacing of 1.05 nm but remains within the error margin, however when in the polymerase environment, 8-oxoguanine and the canonical adenine - thymine spacing match at 1.11-1.12nm spacing while 8-oxoguanine is located on the template strand, but is disrupted by tyrosine 251 while situated on the triphosphate strand.

We observe that 8-oxoguanine, when paired with adenine in polymerase {\lambda}, can mimic the adenine-thymine structure, as predicted in experimental results, and thus would be misincorporated, but is strongly dependent on its conformation.