Polarizable Models for Selected Endocrine Disrupting Chemicals and Their Hosts

Steroid hormones like estradiol and progesterone bind to nuclear hormone receptors and regulate gene transcription. They compete with pollutants and Endocrine Distrupting Chemicals (EDCs) like bisphenol A. When administered as medication, estradiol and progesterone are themselves considered EDCs. To allow modeling studies, parameters for the polarizable AMOEBA force field were derived here for these three molecules, along with the host molecule cyclodextrin and two phosphorylated forms of p-cresol and tyrosine. Indeed, phosphorylation of an estrogen receptor tyrosine regulates estradiol action. AMOEBA-optimized molecular structures were in good agreement with quantum mechanics, and interaction energies with water or ammonium were well-reproduced. Molecular dynamics simulations of crystal structures showed improved agreement with experiment over an additive force field; the mean relative error for unit cell volumes was reduced by more than two. A short MD simulation of the estradiol-estrogen receptor complex was done as a proof of principle and was structurally stable. Although additional simulations are desirable, the developed parameters should already be useful for studying hormone and EDC interactions with their hosts.