Exploring the folding free energy landscape of insulin using bias exchange metadynamics. J Phys Chem B 2009 Mar 19;113(11):3556-64
Date
02/27/2009Pubmed ID
19243106DOI
10.1021/jp809776vScopus ID
2-s2.0-65249172627 (requires institutional sign-in at Scopus site) 42 CitationsAbstract
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.
Author List
Todorova N, Marinelli F, Piana S, Yarovsky IAuthor
Fabrizio Marinelli PhD Associate Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AlgorithmsAmino Acid Sequence
Crystallography, X-Ray
Insulin
Kinetics
Models, Molecular
Protein Conformation
Protein Folding
Thermodynamics
