Photoactivation of Cryptochromes from <i>Drosophila melanogaster</i> and <i>Sylvia borin</i>: Insight into the Chemical Compass Mechanism by Computational Investigation

Although behavioral studies demonstrated light-induced magnetoreception in the insect <i>Drosophila melanogaster</i>, gaining insight into the possibility that a radical-pair mechanism accounts for the magnetic response of the cryptochrome (DmCry1) is complicated by a number of factors. In addition, the mechanism of magnetoreception for the cryptochrome from the garden warbler bird <i>Sylvia borin</i> (gwCry1a), which demonstrated a long-lived radical pair by transient optical absorption measurements, has also not been rationalized. To assess potential feasibility of a radical-pair mechanism in DmCry1 and gwCry1a, formed by excitation and electron transfer between a Trp-triad and flavin adenine dinucleotide (FAD), further separated by electron transfer within the triad, we applied a combination of theoretical methods, including homology modeling and molecular dynamics (MD) for structure refinement, high-level ab initio theory, and MD simulations using a polarizable force-field for prediction of p<i>K</i>_a and the electron transfer rate. Calculated excitation energies, followed by electron transfer in model compounds of DmCry1 that assume proton transfer in conjunction with electron transfer from Trp (W420) to FAD and the predicted p<i>K</i>_a for the proximate residue to FAD (Cys416), support a radical-pair mechanism. Furthermore, free-energy and reorganization energies for the Trp-triad in DmCry1 demonstrate facile electron transfer, explained by the local protein environment and exposure to solvent, which in turn enables a large enough distance separation for the radical-pair partners. Results for gwCry1a demonstrated the importance of accounting for relaxed excited-state geometries in validating the first stage of a radical-pair mechanism. This work provides insight into the so-called chemical compass mechanism to explain magnetic-field sensing in DmCry1 and gwCry1a, expanding on previous work on the cyrptochrome from the plant <i>Arabidopsis thaliana</i> (Solov’yov et al. <i>J. Am. Chem. Soc.</i> <b>2012</b>, <i>134</i>, 18046–18052. Solov’yov et al., <i>Sci. Rep.</i> <b>2014</b>, <i>4</i>, 1–8.)