ESPE Abstracts (2022) 95 P1-30

ESPE2022 Poster Category 1 Bone, Growth Plate and Mineral Metabolism (46 abstracts)

Vitamin D may facilitate Clock/Bmal1-DNA interactions in a Vitamin D receptor-independent fashion

Nicolas Nicolaides 1 , Eleni Papakonstantinou 2 , Dimitrios Vlachakis 2 & George Chrousos 3

1Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, ‘Aghia Sophia’ Children’s Hospital, Athens, Greece; 2Genetics and Computational Biology Group, Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, Athens, Greece; 3University Research Institute on Maternal and Child Health and Precision Medicine, National and Kapodistrian University of Athens Medical School, ‘Aghia Sophia’ Children’s Hospital, Athens, Greece

Background: The Clock/Bmal1 transcription factor heterodimer regulates the circadian activities of many biological systems, including the hypothalamic-pituitary-adrenal (HPA) axis, by trans-activating or trans-repressing downstream target genes. 1,25 Dihydroxy Vitamin D (Vitamin D), a sterol hormone that is activated by exposure to sunlight, plays a fundamental role in maintaining calcium and phosphorus homeostasis. Recent evidence suggests that the nuclear vitamin D receptor (VDR) interacts with the Clock component of the heterodimer, thereby influencing the binding of the latter onto the regulatory regions of its target genes in a circadian fashion. However, direct influence of vitamin D on the transcriptional activity of the Clock/Bmal1 has not been investigated as yet. Direct influence of the steroid hormone cortisol on the interaction of the heterodimer with double stranded (ds) DNA was previously shown.

Objective and Hypotheses: To investigate in silico the potential role of light-activated vitamin D in the Clock/Bmal1 heterodimer complex-generated circadian biorhythms. For comparison, cortisol was studied in parallel.

Methods and Results: The complex of Clock/Bmal1 was modeled via conventional molecular modeling techniques and used to perform molecular docking experiments for vitamin D and cortisol. Experimentally determined structures and the constructed models were then used for molecular docking with ZDOCK version 3.0. Molecular systems were subjected to unrestrained Molecular Dynamics simulations (MDS) using the Gromacs suite, version 4.5.5. MDS took place in a SPC water-solved, periodic environment. Water molecules were added using the truncated octahedron box extending 7Å from each atom. Molecular systems were neutralized with counter-ions as required. For the purposes of this study, all MDS were performed using the NVT ensemble in a canonical environment, at 300 K, 1 atm, and a step size equal to 2 femtoseconds for a total 100 nanoseconds simulation time. An NVT ensemble requires that the Number of atoms, Volume, and Temperature remain constant throughout the simulation. We found that upon vitamin D and cortisol binding, the two alpha-helices bend inward from the network of the established hydrogen, van de Waals, and weak bonds. Notably, vitamin D formed more bonds than cortisol, thus, achieving a more stable docking conformation with dsDNA than the latter.

Conclusions:Our results indicate that vitamin D levels may enhance Clock/Bmal1-dsDNA interactions, potentially serving in an ultrashort positive feedback loop between this hormone and the circadian clock during the morning hours.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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