| Julien Pecher1, Guillaume Le Flem2, Patrick Bogdanowicz2, Jean-Pierre Pujol2, David A. Case3, Jacques Rochette1, and Francois-Yves Dupradeau4. (1) DMAG EA 3901 INERIS, Faculte de Pharmacie et de Medecine, Amiens, France, (2) LBTC EA 3214, Faculte de Medecine, Caen, Caen, France, (3) Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA, (4) DMAG EA 3901 INERIS & The Scripps Research Institute, Department of Molecular Biology, 10550 N. Torrey Pines Road, La Jolla, CA |
| Previous studies in our laboratory have demonstrated that an insulin A-chain analog presents similar functional properties to insulin in vitro. In this derivative, the cysteines 7 and 20 implied in the two interchain disulfide bridges have been replaced by two serines, and the intra-A-chain disulfide bridge has been reconstituted. In aqueous solutions, the structure of this oligopeptide remains unknown because of its aggregation property observed over time. Consequently, the folding and structure of this peptide have been studied by Molecular Dynamics using the Generalized Born implicit solvation model implemented in the AMBER8 program. Starting from an extended conformation, a stable tertiary structure for this A-chain analog close to that observed in native insulin is detected. The disulfide bridge strongly stabilizes the central loop, and the two characteristic alpha helices are formed. These results confirm that the isolated A-chain can spontaneously adopt its tertiary structure. The tridimensional structure observed could be the one which interacts with the insulin receptor and raises the fundamental question of the role of the B-chain in insulin. |
