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 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.
The ability of migratory birds to sense magnetic fields has been known for decades, although the understanding of the underlying mechanism is still elusive. Currently, the strongest magnetoreceptor candidate in birds is a protein called cryptochrome 4a. The cryptochrome 4a protein has changed through evolution, apparently endowing some birds with a more pronounced magnetic sensitivity than others. Using phylogenetic tools, we show that a specific tryptophan tetrad and a tyrosine residue predicted to be essential for cryptochrome activation are highly conserved in the avian clade. Through state-of-the-art molecular dynamics simulations and associated analyses, we also studied the role of these specific residues and the associated mutants on the overall dynamics of the protein. The analyses of the single residue mutations were used to judge how far a local change in the protein structure can impact specific dynamics of European robin cryptochrome 4a. We conclude that the replacements of each of the tryptophans one by one with a phenylalanine do not compromise the overall stability of the protein.
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