Abstract
Interconnected transcriptional and translational feedback loops are at the core of the molecular mechanism of the circadian clock. Such feedback loops are synchronized to external light entrainment by the blue light photoreceptor cryptochrome (CRY) that undergoes conformational changes upon light absorption by an unknown photoexcitation mechanism. Light-induced charge transfer (CT) reactions in Drosophila CRY (dCRY) are investigated by state-of-the-art simulations that reveal a complex, multi-redox site nature of CT dynamics on the microscopic level. The simulations consider redox-active chromophores of the tryptophan triad (Trp triad) and further account for pathways mediated by W314 and W422 residues proximate to the C-terminal tail (CTT), thus avoiding a pre-bias to specific W-mediated CT pathways. The conducted dissipative quantum dynamics simulations employ microscopically derived model Hamiltonians and display complex and ultrafast CT dynamics on the picosecond timescale, subtly balanced by the electrostatic environment of dCRY. In silicio point mutations provide a microscopic basis for rationalizing particular CT directionality and demonstrate the degree of electrostatic control realized by a discrete set of charged amino acid residues. The predicted participation of CT states in proximity to the CTT relates the directionality of CT reactions to the spatial vicinity of a linear interaction motif. The results stress the importance of CTT directional charge transfer in addition to charge transfer via the Trp triad and call for the use of full-length CRY models including the interactions of photolyase homology region (PHR) and CTT domains.
Highlights
Cryptochromes (CRYs) are highly conserved flavoproteins that share great sequence and structural homology to photolyases but lack their DNA repairing function [1,2,3]
The root mean square displacements (RMSD) of the C-terminal tail (CTT) domain shows conformational reorganization between two distinct conformational states on a time period of ≈20–30 ns around the Drosophila CRY (dCRY) RMSD
The findings reveal the importance of charge transfer (CT) dynamics involving ADE and W moieties proximate to the CTT (ISO− ADE+, ISO− W314+ and ISO− W422+ ) in addition to conventional Trp triad mediated CT and suggest that the ADE moiety actively participates in the initial steps of charge separation
Summary
Cryptochromes (CRYs) are highly conserved flavoproteins that share great sequence and structural homology to photolyases but lack their DNA repairing function [1,2,3]. CRYs play a central role in the regulation of the circadian cycle of bacteria, plants, and animals. The blue light photoreceptor CRY [4] synchronizes the master circadian clock to external stimuli, i.e., incident sunlight by regulating the abundance of the clock protein Timeless (TIM) via its targeting for ubiquitin-mediated degradation [5]. CRY consist of an N-terminal photolyase homology region (PHR) that binds the flavin adenine dinucleotide (FAD) cofactor, and a variable C-terminal tail (CTT) that shows high diversity in amino acid sequences among organisms [6,7,8]. Upon blue light illumination CRY binds to TIM and the light-dependent recognition of Molecules 2020, 25, 4810; doi:10.3390/molecules25204810 www.mdpi.com/journal/molecules
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