Abstract
Herein, we deploy an in silico pipeline of structural bioinformatics, thermodynamics, and molecular dynamics to investigate the role of cortisol in circadian rhythms, biorhythms, stress response, and even sleep disorders. Our study shows that high concentrations of cortisol intercalate in the minor groove of DNA. This phenomenon widens the adjacent major grooves and provides the Clock/Bmal1 complex with more space to dock and interact with DNA. Then, the strong charges of cortisol pull the alpha helices of the Clock/Bmal1 complex and bend it inward, thus establishing stronger interactions and prolonged signaling. Our results indicate that elevated cortisol levels play an important role in stress, inflammation, and sleep disorders as a result of prolonged and stronger dsDNA – Clock/Bmal1 interactions.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Amidi A, Amidi S, Vlachakis D, Paragios N, Zacharaki EI (2016) A machine learning methodology for enzyme functional classification combining structural and protein sequence descriptors. 9656. https://doi.org/10.1007/978-3-319-31744-1_63
Amidi S, Amidi A, Vlachakis D, Paragios N, Zacharaki EI (2017) Automatic single- and multi-label enzymatic function prediction by machine learning. PeerJ 5:e3095. https://doi.org/10.7717/peerj.3095
Anafi RC et al (2014) Machine learning helps identify CHRONO as a circadian clock component. PLoS Biol 12:e1001840. https://doi.org/10.1371/journal.pbio.1001840. PBIOLOGY-D-13-03396 [pii]
Annayev Y, Adar S, Chiou YY, Lieb JD, Sancar A, Ye R (2014) Gene model 129 (Gm129) encodes a novel transcriptional repressor that modulates circadian gene expression. J Biol Chem 289:5013–5024. https://doi.org/10.1074/jbc.M113.534651. M113.534651 [pii]
Balatsos NAA et al (2009) Competitive inhibition of human poly(a)-specific ribonuclease (PARN) by synthetic fluoro-pyranosyl nucleosides. Biochemistry 48:6044–6051. https://doi.org/10.1021/bi900236k
Balatsos N, Vlachakis D, Chatzigeorgiou V, Manta S, Komiotis D, Vlassi M, Stathopoulos C (2012) Kinetic and in silico analysis of the slow-binding inhibition of human poly(a)-specific ribonuclease (PARN) by novel nucleoside analogues. Biochimie 94:214–221. https://doi.org/10.1016/j.biochi.2011.10.011
Boulaki V, Vlachakis D, Sotiraki S, Kossida S (2018) An up-to-date review of piglet isosporosis: new insights and therapeutic perspectives. In: Veterinary science: breakthroughs in research and practice, pp 116–131. https://doi.org/10.4018/978-1-5225-5640-4.ch006
Brancale A, Vlachaki C, Vlachakis D (2008) Molecular modelling study of the 3D structure of the bovine viral diarrhea virus (BVDV) helicase. In Silico Biol 8:461–469
Carvalho CS, Vlachakis D, Tsiliki G, Megalooikonomou V, Kossida S (2013) Protein signatures using electrostatic molecular surfaces in harmonic space. PeerJ 1:e185. https://doi.org/10.7717/peerj.185
Charmandari E, Tsigos C, Chrousos G (2005) Endocrinology of the stress response. Annu Rev Physiol 67:259–284. https://doi.org/10.1146/annurev.physiol.67.040403.120816
Chatzikonstantinou M, Vlachakis D, Chronopoulou E, Papageorgiou L, Papageorgiou AC, Labrou NE (2017) The glutathione transferase family of Chlamydomonas reinhardtii: identification and characterization of novel sigma class-like enzymes. Algal Res 24:237–250. https://doi.org/10.1016/j.algal.2017.03.010
Chong SYC, Xin L, Ptacek LJ, Fu YH (2018) Disorders of sleep and circadian rhythms. Handb Clin Neurol 148:531–538. https://doi.org/10.1016/B978-0-444-64076-5.00034-X. B978-0-444-64076-5.00034-X [pii]
Chrousos GP (2009) Stress and disorders of the stress system. Nat Rev Endocrinol 5:374–381. https://doi.org/10.1038/nrendo.2009.106. nrendo.2009.106 [pii]
Chrousos GP, Gold PW (1992) The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 267:1244–1252
Chrousos GP, Kino T (2005) Intracellular glucocorticoid signaling: a formerly simple system turns stochastic. Sci Signal 2005:pe48. https://doi.org/10.1126/stke.3042005pe48. stke.3042005pe48 [pii]
Chrousos G, Vgontzas AN, Kritikou I (2000) HPA axis and sleep. NBK279071 [bookaccession]
Dalkas GA, Vlachakis D, Tsagkrasoulis D, Kastania A, Kossida S (2013) State-of-the-art technology in modern computer-aided drug design. Brief Bioinform 14:745–752. https://doi.org/10.1093/bib/bbs063
Goriki A et al (2014) A novel protein, CHRONO, functions as a core component of the mammalian circadian clock. PLoS Biol 12:e1001839. https://doi.org/10.1371/journal.pbio.1001839. PBIOLOGY-D-13-03433 [pii]
Kandil S et al (2009) Discovery of a novel HCV helicase inhibitor by a de novo drug design approach. Bioorg Med Chem Lett 19:2935–2937. https://doi.org/10.1016/j.bmcl.2009.04.074
Kiyohara YB et al (2006) The BMAL1 C terminus regulates the circadian transcription feedback loop. Proc Natl Acad Sci U S A 103:10074–10079. https://doi.org/10.1073/pnas.0601416103. 0601416103 [pii]
Ko CH, Takahashi JS (2006) Molecular components of the mammalian circadian clock. Hum Mol Genet 15(2):R271–R277. https://doi.org/10.1093/hmg/ddl207. 15/suppl_2/R271 [pii]
Kondratov RV, Kondratova AA, Lee C, Gorbacheva VY, Chernov MV, Antoch MP (2006) Post-translational regulation of circadian transcriptional CLOCK(NPAS2)/BMAL1 complex by CRYPTOCHROMES. Cell Cycle 5:890–895. https://doi.org/10.4161/cc.5.8.2684. 2684 [pii]
Marinou M, Platis D, Ataya FS, Chronopoulou E, Vlachakis D, Labrou NE (2018) Structure-based design and application of a nucleotide coenzyme mimetic ligand: application to the affinity purification of nucleotide dependent enzymes. J Chromatogr A. https://doi.org/10.1016/j.chroma.2018.01.009
Nader N, Chrousos GP, Kino T (2010) Interactions of the circadian CLOCK system and the HPA axis. Trends Endocrinol Metab 21:277–286. https://doi.org/10.1016/j.tem.2009.12.011. S1043-2760(10)00002-0 [pii]
Nicolaides NC, Galata Z, Kino T, Chrousos GP, Charmandari E (2010) The human glucocorticoid receptor: molecular basis of biologic function. Steroids 75:1–12. https://doi.org/10.1016/j.steroids.2009.09.002. S0039-128X(09)00208-6 [pii]
Nicolaides NC et al (2015a) A novel mutation of the hGR gene causing Chrousos syndrome. Eur J Clin Investig 45:782–791. https://doi.org/10.1111/eci.12470
Nicolaides NC, Kyratzi E, Lamprokostopoulou A, Chrousos GP, Charmandari E (2015b) Stress, the stress system and the role of glucocorticoids. Neuroimmunomodulation 22:6–19. https://doi.org/10.1159/000362736. 000362736 [pii]
Nicolaides NC et al (2016) Functional characterization of the hGRαT556I causing Chrousos syndrome. Eur J Clin Investig 46:42–49. https://doi.org/10.1111/eci.12563
Nicolaides NC, Charmandari E, Kino T, Chrousos GP (2017) Stress-related and circadian secretion and target tissue actions of glucocorticoids: impact on health. Front Endocrinol (Lausanne) 8:70. https://doi.org/10.3389/fendo.2017.00070
Padmanabhan K, Robles MS, Westerling T, Weitz CJ (2012) Feedback regulation of transcriptional termination by the mammalian circadian clock PERIOD complex. Science 337:599–602. https://doi.org/10.1126/science.1221592. science. 1221592[pii]
Palaiomylitou M, Tartas A, Vlachakis D, Tzamarias D, Vlassi M (2008) Investigating the structural stability of the Tup1-interaction domain of Ssn6: evidence for a conformational change on the complex. Proteins Struct Funct Genet 70:72–82. https://doi.org/10.1002/prot.21489
Papageorgiou L, Loukatou S, Koumandou VL, Makałowski W, Megalooikonomou V, Vlachakis D, Kossida S (2014) Structural models for the design of novel antiviral agents against Greek Goat Encephalitis. PeerJ 2:e664. https://doi.org/10.7717/peerj.664
Papageorgiou L, Loukatou S, Sofia K, Maroulis D, Vlachakis D (2016) An updated evolutionary study of Flaviviridae NS3 helicase and NS5 RNA-dependent RNA polymerase reveals novel invariable motifs as potential pharmacological targets. Mol BioSyst 12:2080–2093. https://doi.org/10.1039/c5mb00706b
Papageorgiou L, Megalooikonomou V, Vlachakis D (2017) Genetic and structural study of DNA-directed RNA polymerase II of Trypanosoma brucei, towards the designing of novel antiparasitic agents. PeerJ 2017. https://doi.org/10.7717/peerj.3061
Robinson R (2014) Chronos: stress makes the clock tick. PLoS Biol 12:e1001838. https://doi.org/10.1371/journal.pbio.1001838. PBIOLOGY-D-14-00806 [pii]
Schnerch J et al (2016) Functional toll-like receptor 9 expression and CXCR3 ligand release in pulmonary sarcoidosis. Am J Respir Cell Mol Biol 55:749–757. https://doi.org/10.1165/rcmb.2015-0278OC
Sellis D, Drosou V, Vlachakis D, Voukkalis N, Giannakouros T, Vlassi M (2012) Phosphorylation of the arginine/serine repeats of Lamin B receptor by SRPK1-insights from molecular dynamics simulations. Biochim Biophys Acta Gen Subj 1820:44–55. https://doi.org/10.1016/j.bbagen.2011.10.010
Sertedaki A et al (2016) Functional characterization of two novel germline mutations of the KCNJ5 gene in hypertensive patients without primary aldosteronism but with ACTH-dependent aldosterone hypersecretion. Clin Endocrinol 85:845–851. https://doi.org/10.1111/cen.13132
Tagkalakis F, Vlachakis D, Megalooikonomou V, Skodras A (2017) A novel approach to finger vein authentication. In: Proceedings – international symposium on biomedical imaging, pp 659–662. https://doi.org/10.1109/isbi.2017.7950606
Takahashi JS, Hong HK, Ko CH, McDearmon EL (2008) The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nat Rev Genet 9:764–775. https://doi.org/10.1038/nrg2430. nrg2430 [pii]
Theoharaki C et al. (2018) Delineation of the functional and structural properties of the glutathione transferase family from the plant pathogen Erwinia carotovora functional and integrative. Genomics 1–12. https://doi.org/10.1007/s10142-018-0618-8
Vangelatos I, Vlachakis D, Sophianopoulou V, Diallinas G (2009) Modelling and mutational evidence identify the substrate binding site and functional elements in APC amino acid transporters. Mol Membr Biol 26:356–370. https://doi.org/10.1080/09687680903170546
Vlachakis D (2009) Theoretical study of the Usutu virus helicase 3D structure, by means of computer-aided homology modelling. Theor Biol Med Model 6. https://doi.org/10.1186/1742-4682-6-9
Vlachakis D, Kossida S (2013) Molecular modeling and pharmacophore elucidation study of the classical swine fever virus helicase as a promising pharmacological target. PeerJ 1:e85. https://doi.org/10.7717/peerj.85
Vlachakis D, Pavlopoulou A, Tsiliki G, Komiotis D, Stathopoulos C, Balatsos NAA, Kossida S (2012) An integrated in silico approach to design specific inhibitors targeting human poly(a)-specific ribonuclease. PLoS One 7. https://doi.org/10.1371/journal.pone.0051113
Vlachakis D, Kontopoulos DG, Kossida S (2013a) Space constrained homology modelling: the paradigm of the RNA-dependent RNA polymerase of dengue (type II) virus. Comput Math Methods Med 2013. https://doi.org/10.1155/2013/108910
Vlachakis D, Koumandou VL, Kossida S (2013b) A holistic evolutionary and structural study of flaviviridae provides insights into the function and inhibition of HCV helicase. PeerJ:1, e74. https://doi.org/10.7717/peerj.74
Vlachakis D, Pavlopoulou A, Kazazi D, Kossida S (2013c) Unraveling microalgal molecular interactions using evolutionary and structural bioinformatics. Gene 528:109–119. https://doi.org/10.1016/j.gene.2013.07.039
Vlachakis D, Tsiliki G, Kossida S (2013d) 3D molecular modelling of the helicase enzyme of the endemic, Zoonotic Greek Goat Encephalitis virus. Commun Comput Inf Sci 383. https://doi.org/10.1007/978-3-642-41013-0_17
Vlachakis D, Tsiliki G, Pavlopoulou A, Roubelakis MG, Champeris Tsaniras S, Kossida S (2013e) Antiviral stratagems against HIV-1 using RNA interference (RNAi) technology. Evol Bioinforma 2013:203–213. https://doi.org/10.4137/ebo.s11412
Vlachakis D, Pavlopoulou A, Roubelakis MG, Feidakis C, Anagnou NP, Kossida S (2014) 3D molecular modeling and evolutionary study of the trypanosoma brucei DNA topoisomerase IB, as a new emerging pharmacological target. Genomics 103:107–113. https://doi.org/10.1016/j.ygeno.2013.11.008
Vlachakis D, Armaos A, Kossida S (2017) Advanced protein alignments based on sequence, structure and hydropathy profiles; the paradigm of the viral polymerase enzyme. Math Comput Sci 11:197–208. https://doi.org/10.1007/s11786-016-0287-8
Wang Z, Wu Y, Li L, Su XD (2013) Intermolecular recognition revealed by the complex structure of human CLOCK-BMAL1 basic helix-loop-helix domains with E-box DNA. Cell Res 23:213–224. https://doi.org/10.1038/cr.2012.170. cr2012170 [pii]
Funding Statement
DV would like to acknowledge the funding received from (i) Microsoft Azure for Genomics Research Grant (CRM:0740983); (ii) FrailSafe Project (H2020-PHC-21-2015 – 690140) “Sensing and predictive treatment of frailty and associated co-morbidities using advanced personalized models and advanced interventions,” co-funded by the European Commission under the Horizon 2020 research and innovation program; and (iii) Amazon Web Services Cloud for Genomics Research Grant (309211522729).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2020 Springer Nature Switzerland AG
About this paper
Cite this paper
Raftopoulou, S. et al. (2020). Structural Study of the DNA: Clock/Bmal1 Complex Provides Insights for the Role of Cortisol, hGR, and HPA Axis in Stress Management and Sleep Disorders. In: Vlamos, P. (eds) GeNeDis 2018. Advances in Experimental Medicine and Biology, vol 1195. Springer, Cham. https://doi.org/10.1007/978-3-030-32633-3_10
Download citation
DOI: https://doi.org/10.1007/978-3-030-32633-3_10
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-32632-6
Online ISBN: 978-3-030-32633-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)