Let’s Talk about Sex Hormone Receptors and Their Physical Interaction with Sonic Hedgehog Protein: A Computational Study with Emphasis on Progesterone Receptor

Abstract

The mature form of the sonic hedgehog protein (SHH-N) is the main canonical activator of the Hedgehog-GLI signaling pathway whose aberrant activity can lead to the development of hormone-dependent cancers like breast or prostate cancer. In this study, we employed computational methods to explore the potential binding of SHH-N with the progesterone receptor (PR), the sole member of the nuclear sex hormone receptor (SHRs) subfamily not previously linked to SHH-N. Through a combination of molecular docking, robust molecular dynamics (MD) simulations, and free energy calculations, we predicted a stable binding between SHH-N-cholesterol and PR. To validate our findings, we extended our in silico investigation to encompass the complexes between SHH-N-cholesterol and estrogen receptor alpha (ERα) and androgen receptor (AR)—complexes that have been experimentally confirmed in our prior studies. The calculations not only confirmed the stable binding of SHH-N-cholesterol with both ERα and AR but also revealed the strongest binding occurred with ERα, followed by AR and PR, suggesting a non-canonical interaction with potential biological significance. Microsecond-long MD simulations unveiled tight cholesterol binding in the SHRs’ binding sites, and we gained insights into sub-molecular interactions contributing to protein-protein stabilization in complexes involving PR and ERα for the first time. The MM/PBSA calculations indicated comparable binding affinities of PR for progesterone and SHH-N-cholesterol, with ERα exhibiting a more favorable enthalpy of binding with SHH-N-cholesterol than with estradiol.