The binding mode of progesterone to its receptor deduced from molecular dynamics simulations.
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.
Mordasini
Tiziana
T
IBM Research, Zurich Research Laboratory, 8803 Rüschlikon, Switzerland.
Curioni
Alessandro
A
Bursi
Roberta
R
Andreoni
Wanda
W
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*
D011980:Receptors, Progesterone; D011374:Progesterone