title: Exploring the folding free energy landscape of insulin using bias exchange metadynamics.
abstract: The bias exchange metadynamics (BE-META) technique was applied to investigate the folding mechanism of insulin, one of the most studied and biologically important proteins. The BE-META simulations were performed starting from an extended conformation of chain B of insulin, using only eight replicas and seven reaction coordinates. The folded state, together with the intermediate states along the folding pathway were identified and their free energy was determined. Three main basins were found separated from one another by a large free energy barrier. The characteristic native fold of chain B was observed in one basin, while the other two most populated basins contained "molten-globule" conformations stabilized by electrostatic and hydrophobic interactions, respectively. Transitions between the three basins occur on the microsecond time scale. The implications and relevance of this finding to the folding mechanisms of insulin were investigated.
authors.affiliation: Applied Physics, School of Applied Sciences, RMIT University, Melbourne, Victoria, Australia.
authors.forename: Nevena
authors.initials: N
authors.lastname: Todorova
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Marinelli
authors.forename: Stefano
authors.initials: S
authors.lastname: Piana
authors.forename: Irene
authors.initials: I
authors.lastname: Yarovsky
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D007328:Insulin / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D011487:Protein Conformation; D017510:Protein Folding; D013816:Thermodynamics
chemical_list: D007328:Insulin