What Computational Simulations Tell Us about Cryptochromes in Magnetoreception
- 1Scuola Normale Superiore, Piazza dei Cavalieri 7, 56126 Pisa, Italy
- 2Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via G. Moruzzi 13, 56124 Pisa, Italy
Abstract
The ability of migratory birds to orient using the Earth’s magnetic field has been proposed to rely on a radical-pair mechanism operating within Cryptochrome 4, a blue-light flavoprotein. In this perspective, we review how computational approaches have shaped our molecular understanding of cryptochrome-based magnetoreception. We organize the discussion around the three steps that connect light absorption to a cellular signal: the photochemical step, in which light absorption by FAD drives a hole-hopping electron-transfer cascade along a conserved tryptophan tetrad; the spin-dependent step, in which the resulting radical pair interconverts between singlet and triplet states under the influence of the magnetic field; and the structural step, in which this transient information is converted into a long-lived signaling state. The early electron-transfer events are now described with growing confidence and appear conserved across avian orthologs, although the relative stability of the final radical-pair states remains debated. The spin-dependent step remains more problematic: once the fluctuations of the hyperfine couplings and a realistic number of nuclear spins are included, the predicted magnetic sensitivity at geomagnetic field intensities becomes very small, and explaining the magnitude of the effect is still a central open problem. The postactivation conformational dynamics, involving intrinsically disordered regions, remains the principal challenge. We suggest that atomistic multiscale modeling, integrated with artificial intelligence-based approaches, has become indispensable for connecting the conserved photochemistry to this downstream process.
Related
- Small genomes, big lessons: what viruses teach us about structure-based riboregulation
- Advancing asparaginase-based therapy for acute lymphoblastic leukemia through computational immunoengineering and molecular dynamics simulations
- 1017 Computational design of de novo antigen-specific T cell receptors using AI optimization and long-time-scale molecular simulations for targeted cancer immunotherapy
- Ascending at Dawn, Descending at Dusk: Could Changes in Light and Oxygen Enhance Radical-Pair Magnetoreception in Migratory Birds?
- Experimental platform to study the neuronal mechanisms of magnetoreception in the honey bee
BibTeX
@article{cascone2026what,
title = {{What Computational Simulations Tell Us about Cryptochromes in Magnetoreception}},
author = {Mariastella Cascone and Lorenzo Cupellini and Benedetta Mennucci},
journal = {Biochemistry},
year = {2026},
month = oct,
doi = {10.1021/acs.biochem.6c00516},
url = {https://doi.org/10.1021/acs.biochem.6c00516},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - What Computational Simulations Tell Us about Cryptochromes in Magnetoreception
AU - Mariastella Cascone
AU - Lorenzo Cupellini
AU - Benedetta Mennucci
PY - 2026
DA - 2026/10/21
JO - Biochemistry
DO - 10.1021/acs.biochem.6c00516
UR - https://doi.org/10.1021/acs.biochem.6c00516
AB - The ability of migratory birds to orient using the Earth’s magnetic field has been proposed to rely on a radical-pair mechanism operating within Cryptochrome 4, a blue-light flavoprotein. In this perspective, we review how computational approaches have shaped our molecular understanding of cryptochrome-based magnetoreception. We organize the discussion around the three steps that connect light absorption to a cellular signal: the photochemical step, in which light absorption by FAD drives a hole-hopping electron-transfer cascade along a conserved tryptophan tetrad; the spin-dependent step, in which the resulting radical pair interconverts between singlet and triplet states under the influence of the magnetic field; and the structural step, in which this transient information is converted into a long-lived signaling state. The early electron-transfer events are now described with growing confidence and appear conserved across avian orthologs, although the relative stability of the final radical-pair states remains debated. The spin-dependent step remains more problematic: once the fluctuations of the hyperfine couplings and a realistic number of nuclear spins are included, the predicted magnetic sensitivity at geomagnetic field intensities becomes very small, and explaining the magnitude of the effect is still a central open problem. The postactivation conformational dynamics, involving intrinsically disordered regions, remains the principal challenge. We suggest that atomistic multiscale modeling, integrated with artificial intelligence-based approaches, has become indispensable for connecting the conserved photochemistry to this downstream process.
SN - 0006-2960
SN - 1520-4995
ER -