Plausible interaction of an alpha-fetoprotein cyclopeptide with the G-protein-coupled receptor model GPR30: docking study by molecular dynamics simulated annealing.

In this manuscript, the procedure of molecular dynamics simulated annealing is applied to locate a probable receptor and binding site of a cyclicpeptide that inhibits estrogen-stimulated proliferation of breast cancer. The hydrophilic cyclopeptide EMTOVNOGQ (O = 4-hydroxyproline), derived from alpha-fetoprotein, is an inhibitor of estrogen-stimulated proliferation of human breast cancer. This peptide has been shown to act through a mechanism different from that of estrogen; however, its receptor is unknown. We report computer experiments that suggest that this peptide may execute its actions by interacting with GPR30, a G-protein-coupled receptor. The subject of this work is the simulation, by molecular dynamics simulated annealing, of the interaction of cyclopeptide EMTOVNOGQ with receptor GPR30 protein. A conformational analysis of the cyclopeptide was undertaken and the final structure was docked on several sites of the GPR30 3D model. Our results show that the cyclopeptide interacts on the pocket located between TM6 and TM7 transmembrane helices of the G-protein, triggering a slight conformational change in the secondary structure of the receptor in the complex. Based on differences in accessible surface areas between GPR30 and its ligand, the residues in the interaction zone were identified. The cyclopeptide is stabilized in the active site by forming a network of hydrogen bonds between Glu, Thr, (1)Pro(OH) and GLn residues of the ligand and Arg-259, Cys-271, Asn-316, Asn-320 and Tyr-324 of the G-protein. Moreover, the study of the electrostatic surface potential on the GPR30 receptor shows that the active site is more positively charged than the other sites. Our modeling indicates a plausible interaction of the cyclopeptide with the seven transmembrane GPR30 protein. This may have profound implications for the treatment of breast cancer.