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 contrasts chemical intuition and the results of site-directed mutagenesis experiments. Here we report on 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.
By: Tiziana Mordasini, Alessandro Curioni, Roberta Bursi and Wanda Andreoni
Published in: ChemBioChem, volume 4, (no 2-3), pages 155-61 in 2003
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