Background: The circadian rhythm-generating peripheral Clock/Bmal1 heterodimer complex regulates the circadian activities of many biological systems, including the hypothalamic-pituitary-adrenal (HPA) axis, by trans-activating or trans-repressing downstream target genes.
Objective and Hypotheses: To investigate the potential role of elevated cortisol in Clock/Bmal1 heterodimer complex-generated circadian biorhythms, both during its normal early morning circadian surge and during the stress response.
Methods and Results: We deployed an in silico pipeline of structural bioinformatics, thermodynamics and molecular dynamics. Our study showed that at high concentrations, cortisol intercalates into the minor grooves of dsDNA. This widens the adjacent major grooves and allows to the Clock/Bmal1 heterodimer complex more space to dock in and to interact with dsDNA. Then, the high electrical charge of cortisol appears to attract the alpha helices of the Clock/Bmal1 complex, bending it inwards and establishing stronger interactions with the dsDNA. This may result in a stronger and more prolonged signaling of the biological clock when cortisol is elevated.
Conclusions: Our results indicate that the elevated cortisol levels in the early morning circadian surge and during stress facilitate enhanced and prolonged Clock/Bmal1- dsDNA interactions, potentially serving as an ultrashort positive feedback loop between the biological clock and the HPA axis.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology