Molecular dynamics simulations disclose early stages of the photo-activation of cryptochrome 4

Abstract

Birds appear to be equipped with a light-dependent, radical-pair-based magnetic compass that relies on truly quantum processes. While the identity of the sensory protein has remained speculative, cryptochrome 4 has recently been identified as the most auspicious candidate. Here, we report on allatom molecular dynamics (MD) simulations addressing the structural reorganisations that accompany the photoreduction of the flavin cofactor in the European robin cryptochrome 4 (ErCry4). Extensive MD simulations reveal that the photo-activation of ErCry4 induces large-scale conformational changes on short (hundreds of nanoseconds) timescales. Specifically, the photo-reduction is accompanied with the release of the C-terminal tail, structural rearrangements in the vicinity of the FAD-binding site, and the noteworthy formation of an α-helical segment at the N-terminal part. Some of these rearrangements appear to expose potential phosphorylation sites. We describe the conformational dynamics of the protein using a graph-based approach that is informed by the adjacency of residues and the correlation of their local motions. This approach reveals densely coupled reorganisation entities, i.e. graph communities, which could facilitate an efficient signal transduction due to a high density of hubs. These communities are interconnected by a small number of highly important residues. The network approach clearly identifies the sites restructuring upon photoactivation, which appear as protrusions or delicate bridges in the reorganisation network. We also find that, unlike in the homologous cryptochrome from D. melanogaster, the release of the C-terminal domain does not appear to be correlated with the transposition of a histidine residue close to the FAD cofactor.

One Actor, Multiple Roles: The Performances of Cryptochrome in Drosophila

“…MD simulations have also suggested for the FAD cofactor roles other than photoreduction and CRY activation: the FAD presence would confer to the receptor a more fluctuation-prone behavior, thus decreasing the amount of necessary light input energy for CRY activation (Masiero et al, 2014). Recent studies performed on a longer timescale have revealed that following photoactivation, FAD is released from the FAD-binding pocket, providing evidence that CRY undergoes an inactivation reaction rather than a photocycle (Kutta et al, 2018), in agreement with the reported irreversible nature of the light-induced conformational changes (Ozturk et al, 2009;Kattnig et al, 2018;Lin et al, 2018). The active form of CRY is then able to bind the circadian components TIMELESS (Ceriani et al, 1999) and PERIOD (Rosato et al, 2001).…”

On the optimal relative orientation of radicals in the cryptochrome magnetic compass

“…As a directional response to magnetic fields does not fulfil a known function in plants, this could be interpreted as an outcome of the lack of a corresponding evolutionary incentive. Note, however, that while WC is strong in cryptochromes with a tetrad, the orientation of WC in the homology model for the avian cryptochrome 4 [75,76] is less optimal than that extracted from the crystal structure of the Drosophila cryptochrome. This observation could inspire a variety of interpretations: the homology model or the current approach may have limited predictive power, another driver must be considered, anisotropy is an inappropriate measure of sensitivity or that a different radical pair is at play, to name but a few.…”

“…We have also compared the tryptophans of the triad/tetrad for the established crystal structures of cryptochromes with bound flavin and a homology model of cryptochrome 4 from the European Robin [75,76]. The magnetic field effect anisotropies have been summarized in Table 1.…”

“…The largest anisotropy is seen for WC in DmCry. For the animal-like Cryptochrome from Chlamydomonas reinhardtii (PDB ID: 5ZM0) [77] and the model of the avian cryptochrome 4 [75,76], a smaller anisotropy of 0.16 % and 0.15 % is found, respectively. All other relative orientations yield anisotropies of the order of 0.1 %.…”

Computational analysis of amino acids’ adhesion to the graphene surface

“…The graphene layers with deposited amino acids were neutralized in water using NaCl by assuming the height of the simulation box equal to 45Å. The protocol was largely adopted from earlier MD simulation on similar systems [17][18][19]. Particle mesh Ewald method was used to treat the long-range electrostatics [20,21] with a cutoff distance of 12Å.…”