A widespread hypothesis ascribes the ability of migratory birds to navigate over large distances to an inclination compass realized by the protein cryptochrome in the birds’ retinae. Cryptochromes are activated by blue light, which induces a radical pair state, the spin dynamics of which may become sensitive to earth’s weak magnetic fields. The magnetic information is encoded and passed on to downstream processes by structural rearrangements of the protein, the details of which remain vague. We utilize extensive all-atom molecular dynamics simulations to probe the conformational changes of pigeon cryptochrome 4 upon light activation. The structural dynamics are analyzed based on principal component analysis and with the help of distance matrices, which reveal significant changes in selected inter-residue distances. The results are evaluated and discussed with reference to the protein structure and its putative function as a magnetoreceptor. It is suggested that the phosphate-binding loop could act as a gate controlling the access to the flavin adenine dinucleotide cofactor depending on the redox state of the protein.

A recent study by Xu et al. (Nature, 2021, 594, 535–540) provided strong evidence that cryptochrome 4 (Cry4) is a key protein to endow migratory birds with the magnetic compass sense. The investigation compared the magnetic field response of Cry4 from migratory and nonmigratory bird species and suggested that a difference in magnetic sensitivity could exist. This finding prompted an in-depth investigation into Cry4 protein differences on the structural and dynamic levels. In the present study, the pigeon Cry4 (ClCry4) crystal structure was used to reconstruct the missing avian Cry4 protein structures via homology modeling for carefully selected bird species. The reconstructed Cry4 structure from European robin, Eurasian blackcap, zebra finch, chicken, and pigeon were subsequently simulated dynamically and analyzed. The studied avian Cry4 structures show flexibility in analogous regions pointing to similar activation mechanisms and/or signaling interaction partners. It can be concluded that the experimentally recorded difference in the magnetic field sensitivity of Cry4 from different birds is unlikely to be due to solely intrinsic dynamics of the proteins but requires additional factors that have not yet been identified.

The magnetic compass of migratory birds is thought to rely on a radical pair reaction inside the blue-light photoreceptor protein cryptochrome. The sensitivity of such a sensor to weak external magnetic fields is determined by a variety of magnetic interactions, including electron-nuclear hyperfine interactions. Here, we investigate the implications of thermal motion, focusing on fluctuations in the dihedral and librational angles of flavin adenine dinucleotide (FAD) and tryptophan (Trp) radicals in cryptochrome 4a from European robin (Erithacus rubecula, ErCry4a) and pigeon (Columba livia, ClCry4a) and cryptochrome 1 from the plant Arabidopsis thaliana (AtCry1). Molecular dynamics simulations and density functional theory-derived hyperfine interactions are used to calculate the quantum yield of radical pair recombination dependent on the direction of the geomagnetic field. This quantity and various dynamical parameters are compared for [FAD •− Trp •+ ] in ErCry4a, ClCry4a, and AtCry1, with TrpC or TrpD being the third and fourth components of the tryptophan triad/tetrad in the respective proteins. We find that (i) differences in the average dihedral angles in the radical pairs are small, (ii) the librational motions of TrpC •+ in the avian cryptochromes are appreciably smaller than in AtCry1, (iii) the rapid vibrational motions of the radicals leading to strong fluctuations in the hyperfine couplings affect the spin dynamics depending on the usage of instantaneous or time-averaged interactions. Future investigations of radical pair compass sensitivity should therefore not be based on single snapshots of the protein structure but should include the ensemble properties of the hyperfine interactions.

The remarkable ability of migratory birds to navigate accurately using the geomagnetic field for journeys of thousands of kilometres is currently thought to arise from radical pair reactions inside a protein called cryptochrome. In this article, we explain the quantum mechanical basis of the radical pair mechanism and why it is currently the dominant theory of compass magnetoreception. We also provide a brief account of two important computational simulation techniques that are used to study the mechanism in cryptochrome: spin dynamics and molecular dynamics. At the end, we provide an overview of current research on quantum mechanical processes in avian cryptochromes and the computational models for describing them.

Cryptochromes are a class of light-absorbing proteins that have been shown to be a part of the circadian rhythm of many animals but seem to play a central role for the magnetosensing of migratory birds. Following a documented difference in the sensitivity to an external magnetic field of cryptochrome 4a proteins from migratory and non-migratory birds, a detailed analysis of inter- and intra-protein energetics is called for. The present study relies on classical molecular dynamics simulations of cryptochrome 4a from five avian species to reveal if any of the cryptochromes feature peculiarities in their internal energetics. The five avian cryptochrome 4a proteins from pigeon, European robin, zebra finch, chicken, and Eurasian blackcap are found to be highly similar in respect of their intra-energetic behaviors, while some minor differences between the cryptochromes can be ascribed to the site of specific structural differences. Particular attention has been paid to account for the interaction of the protein with the solvent, and it has been revealed that the solvent could lead to significant stabilization of the chromophore flavin adenine dinucleotide inside of the cryptochrome 4a scaffold.