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Possible Protonation States of Histidines in the Active Site of (6-4) Photolyase

Exposure of cells to UV radiation leads to the formation of different lesions in DNA strands, one of which is a pyrimidine-pyrimidone dimer, also known as (6-4) DNA lesion. (6-4) photolyases are enzymes capable of splitting those dimers back to their corresponding monomers. The crystal structure of this enzyme, isolated from D. melanogaster, has been rather recently solved for the first time, but there are still some open questions concerning the mechanism of the repair. It has been discovered that the crucial role in catalysis is played by two histidines and a tyrosine residue positioned in the active site. First mechanism proposed included formation of an oxetane intermediate, but after crystal structure was described, Carell et al. suggested alternative mechanism, in which one of the histidines is in a protonated state (scheme down). To confirm this assumption, or to find a protonation state that deviates the least from the crystal structure, simulations with 9 different combinations of histidine protonation states were done using Amber9 force field.

(6-4) photolyase ; (6-4) DNA photodamage ; protonation ; histidine

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