Martini 3 Coarse-Grained Models for Steroid Hormones

Steroid hormones are central to the development, metabolism, homeostasis and reproduction of animals and have been the subject of many evolutionary, ecotoxicological and human health studies. Coarse-grain molecular dynamics (CG MD) simulations are a powerful tool to study the structural and dynamic behavior of steroid hormones and their interactions. Here, we expand the capabilities of the widely used Martini 3 CG framework by parameterizing and validating a set of 20 steroid hormone models — including both endogenous and synthetic molecules — to enable their study across diverse targets, systems, and fields of interest. Hormone parameterization followed Martini 3 guidelines, while leveraging the similarities with the parent cholesterol molecule, for which a Martini 3 model is available. Notably, we were able to base our parameterization on the hundreds of experimental structures in the protein data bank that contain steroid hormones, instead of relying on atomistic simulations as is typical with Martini. The parameterized models match to within 5% target molecular volumes, and recover the overall hydrophobicity trend of the hormones, although higher hydrophobicities tended to be overestimated. In free simulations of protein-hormone systems the experimentally known binding poses could be recovered for 89% of the cases, indicating a successful parameterization also from a functional standpoint. Since several Martini 3 protein models were tested, we also incidentally show that the flexibility profile of the OLIVES model is the best suited for this type of protein–ligand recognition. We expect that the availability of our fully validated Martini 3 CG steroid hormone models will contribute to new studies, collaborations, and applications across different scientific fields.