Determinants of Photolyase’s DNA Repair Mechanism in Mesophiles and Extremophiles

Light-driven DNA
repair by extremophilic photolyases is of tremendous
importance for understanding the early development of life on Earth.
The mechanism for flavin adenine dinucleotide repair of DNA lesions
is the subject of debate and has been studied mainly in mesophilic
species. In particular, the role of adenine in the repair process
is poorly understood. Using molecular docking, molecular dynamics
simulations, electronic structure calculations, and electron tunneling
pathways analysis, we examined adenine’s role in DNA repair
in four photolyases that thrive at different temperatures. Our results
indicate that the contribution of adenine to the electronic coupling
between the flavin and the cyclobutane pyrimidine dimer lesion to
be repaired is significant in three (one mesophilic and two extremophilic)
of the four enzymes studied. Our analysis suggests that thermophilic
and hyperthermophilic photolyases have evolved structurally to preserve
the functional position (and thus the catalytic function) of adenine
at their high temperatures of operation. Water molecules can compete
with adenine in establishing the strongest coupling pathway for the
electron transfer repair process, but the adenine contribution remains
substantial. The present study also reconciles prior seemingly contradictory
conclusions on the role of adenine in mesophile electron transfer
repair reactions, showing how adenine-mediated superexchange is conformationally
gated.