Abstract
Photolyases (PLs) are flavoproteins able to repair cross-links formed between adjacent pyrimidine bases in DNA in a light-dependent manner via an electron transfer. The catalytically active redox state of the flavin chromophore for the DNA repair is a fully reduced form of flavin adenine dinucleotide (FADH-). PLs and their relative, cryptochromes (CRYs), share a physicochemical process attributable to the light-dependent reduction of the chromophore via an ultrafast successive electron transfer through exclusively conserved three tryptophan side chains. In some (6-4) PLs and animal CRYs, an additional tryptophan participates in this photoactivation process. In a search for the intrinsic difference between the Trp triad and tetrad, a water molecule proximal to the second and third Trp was found in the reported crystal structure of Arabidopsis thaliana (6-4) PL. Here, we investigated the involvement of the water molecule in photoactivation. Molecular dynamics simulations indicated that the water molecule is stably captured in the binding site, while mutation of S412 increased water displacement from the binding site. Photochemical analysis of recombinant proteins revealed that the S412A mutation significantly decelerated the FAD photoreduction as compared to the wild type. The hydrogen-bonding network including the water molecule would play a key role in the stabilization of the FAD-Trp radical pair.
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