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

Abstract

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 pairing, which has only two internal hydrogen bonds whereas C-G has three hydrogen bonds. It is shown that the third hydrogen bond for A-T is formed when the A-T nucleotide is 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 Ca2+ 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 PO4- ions of adjacent nucleotides and thus bind the steroid molecule directly to the nucleic acid. 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.

Structural Symmetry of DNA Nucleotides and Steroid Hormones

“…The first results associating the steroid molecules and steroid hormones with DNA Nucleotides were presented in my recent work [20] and in this section, illustrations are used to unequivocally document the relation. The section is organized by first presenting the illustrations for structural symmetry of DNA nucleotides with steroid molecules and steroid hormones.…”

“…In the following subsections, molecular models are utilized to support the relationship of the steroid hormone binding and symmetry with DNA nucleotide pairs through an ionic coupling agent, Ca 2+ or Mg 2+ ion, as presented originally in [20]. The relation of the endgroups to the phosphate sugar backbone is presented in Figure 5 for the steroid hormone cortisol.…”

“…The developments presented in this research article indicated calcium ion Ca 2+ as the critical coupling point for the steroid hormone and the DNA nucleotides. As noted in [20], there are several reasons for this implementation, but it is noted that magnesium ion Mg 2+ can also be utilized, because it results in a symmetric coupling with adjacent phosphate groups, as indicated in Figure 14. For this configuration, the distances are tighter: for example, the distance from the phosphate group to the ion at the C17 side is 3.213Å and 3.176Å for magnesium versus 3.469Å and 3.524Å for calcium.…”

“…However, in my recent work [20], a much simpler hypothesis for DNA transcription was developed in which the central tenet is that steroid hormones directly bind to DNA nucleotides in order to enable and initiate DNA transcription. A one-to-one structural correspondence was established between the steroid molecule, steroid hormone and DNA nucleotide pairing, coupled through an ionic mechanism.…”