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

Adv Exp Med Biol. 2020;1195:59-71. doi: 10.1007/978-3-030-32633-3_10.

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.

Keywords: Cell Signaling; Cortisol; DNA intercalation; Genetics; Hypothalamic-pituitary-adrenal (HPA) axis; Inflammation; Sleep disorders; Stress.

MeSH terms

  • ARNTL Transcription Factors / metabolism*
  • CLOCK Proteins / metabolism*
  • Circadian Rhythm / genetics
  • Circadian Rhythm / physiology
  • Computer Simulation
  • DNA / chemistry*
  • DNA / metabolism
  • Humans
  • Hydrocortisone / chemistry
  • Hydrocortisone / metabolism*
  • Hypothalamo-Hypophyseal System / physiology*
  • Inflammation / genetics
  • Inflammation / metabolism
  • Intercalating Agents / chemistry
  • Intercalating Agents / metabolism
  • Pituitary-Adrenal System / physiology*
  • Receptors, Glucocorticoid / metabolism
  • Sleep Wake Disorders / genetics
  • Sleep Wake Disorders / physiopathology*
  • Stress, Psychological / genetics
  • Stress, Psychological / physiopathology
  • Stress, Psychological / prevention & control*

Substances

  • ARNTL Transcription Factors
  • Intercalating Agents
  • Receptors, Glucocorticoid
  • DNA
  • CLOCK Proteins
  • Hydrocortisone