title: The binding mode of progesterone to its receptor deduced from molecular dynamics simulations.
abstract: An unambiguous understanding of the binding mode of human progesterone to its receptor still eludes experimental search. According to the X-ray structure of the ligand-binding domain, only one (O3) of the two keto groups at the ligand ends (O3 and O20) should play a role. This result is in conflict with chemical intuition and the results of site-directed mutagenesis experiments. Herein, we report classical molecular dynamics simulations that reveal the dynamic nature of the binding in solution, elucidate the reasons why X-ray studies failed to determine the role of O20, and clarify the effects of the mutations. The predictive power of the force field is ensured by the consistent introduction of a first-principles representation of the ligand.
authors.affiliation: IBM Research, Zurich Research Laboratory, 8803 Rüschlikon, Switzerland.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mordasini
authors.forename: Alessandro
authors.initials: A
authors.lastname: Curioni
authors.forename: Roberta
authors.initials: R
authors.lastname: Bursi
authors.forename: Wanda
authors.initials: W
authors.lastname: Andreoni
mesh_terms: D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D003198:Computer Simulation; D005260:Female; D006801:Humans; D008958:Models, Molecular; D008967:Molecular Biology / Q000379:methods*; D016297:Mutagenesis, Site-Directed; D011374:Progesterone / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*
chemical_list: D011980:Receptors, Progesterone; D011374:Progesterone