Endogenous Binding of Steroid Molecules to DNA Nucleotides by a Ca2+/PO4- Process to Enable Gene Transcription

Steroid hormones, such as cortisol, testosterone and estrogen, have powerful control over human physiology, growth, and reproduction, but efforts to deploy its potential, such as with glucocorticoids, a first-line defense of inflammation, are often met with severe side effects. Unfortunately, much is unknown about the basic interaction of steroid molecules with DNA, including its receptors, activators, factors, and the gene transcription procedure. In this research article, a remarkable finding is shown for the first time, in which it is illustrated through structural analysis that the base pairings of the four DNA nucleotides, adenine with thymine (A-T) and cytosine with guanine (C-G), form perfectly the classic four ring structure of the steroid molecule, which indicates the profound result put forth in this article that steroid molecules bind directly to DNA for the purpose of gene transcription. Further, critical to a basic understanding of DNA, it is resolved here of the location of the unusual ``missing" hydrogen bond of the A-T and T-A pairings, which has only two internal hydrogen bonds whereas C-G and G-C have three hydrogen bonds. It is shown that the third hydrogen bond for A-T and T-A is formed when the A-T and T-A nucleotides are coupled with corticosteroids, such as cortisol, which has an oxygen functional group that is perfectly positioned to form a hydrogen bond with the accessible oxygen-based functional group of thymine. In addition, to facilitate the binding process, it is shown that Ca$^{2+}$ ions, which are associated with the ligand binding domain of the steroid receptor prior to its association with DNA, couple the oxygen-based functional groups at each end of the steroid molecule with the PO$_4^-$ ions of adjacent nucleotides and thus bind the steroid molecule directly to the nucleic acid. Additionally, the basis of initiating the transcription process is described in which the energy stabilization due to the binding of the ion-steroid complex to DNA is dissipated through the DNA molecule to initiate strand separation locally by increasing the length of hydrogen bonds, thus allowing RNA polymerase action. The results are further amplified by analysis of the cortisol hormone and the ligand binding domain of the glucocorticoid receptor in its interaction with the A-T nucleotide pairing.