title: The mechanism of folding of Im7 reveals competition between functional and kinetic evolutionary constraints.
abstract: Many proteins reach their native state through pathways involving the presence of folding intermediates. It is not clear whether this type of folding landscape results from insufficient evolutionary pressure to optimize folding efficiency, or arises from a conflict between functional and folding constraints. Here, using protein-engineering, ultra-rapid mixing and stopped-flow experiments combined with restrained molecular dynamics simulations, we characterize the transition state for the formation of the intermediate populated during the folding of the bacterial immunity protein, Im7, and the subsequent molecular steps leading to the native state. The results provide a comprehensive view of the folding process of this small protein. An analysis of the contributions of native and non-native interactions at different stages of folding reveals how the complexity of the folding landscape arises from concomitant evolutionary pressures for function and folding efficiency.
authors.affiliation: Astbury Centre for Structural Molecular Biology, University of Leeds, Mount Preston Street, Leeds LS2 9JT, UK.
authors.forename: Claire T
authors.initials: CT
authors.lastname: Friel
authors.forename: D Alastair
authors.initials: DA
authors.lastname: Smith
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
authors.forename: Joerg
authors.initials: J
authors.lastname: Gsponer
authors.forename: Sheena E
authors.initials: SE
authors.lastname: Radford
mesh_terms: D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000378:metabolism*; D007700:Kinetics; D008958:Models, Molecular; D017510:Protein Folding; D017434:Protein Structure, Tertiary
chemical_list: D002352:Carrier Proteins; C509253:E colicin-binding immunity protein Im7, E coli; D029968:Escherichia coli Proteins