title: A detailed unfolding pathway of a (beta/alpha)8-barrel protein as studied by molecular dynamics simulations.
abstract: The (beta/alpha)(8)-barrel is the most common protein fold. Similar structural properties for folding intermediates of (beta/alpha)(8)-barrel proteins involved in tryptophan biosynthesis have been reported in a number of experimental studies; these intermediates have the last two beta-strands and three alpha-helices partially unfolded, with other regions of the polypeptide chain native-like in conformation. To investigate the detailed folding/unfolding pathways of these (beta/alpha)(8)-barrel proteins, temperature-induced unfolding simulations of N-(5'-phosphoribosyl)anthranilate isomerase from Escherichia coli were carried out using a special-purpose parallel computer system. Unfolding simulations at five different temperatures showed a sequential unfolding pathway comprised of several events. Early events in unfolding involved disruption of the last two strands and three helices, producing an intermediate ensemble similar to those detected in experimental studies. Then, denaturation of the first two betaalpha units and separation of the sixth strand from the fifth took place independently. The remaining central betaalphabetaalphabeta module persisted the longest during all simulations, suggesting an important role for this module as the incipient folding scaffold. Our simulations also predicted the presence of a nucleation site, onto which several hydrophobic residues condensed forming the foundation for the central betaalphabetaalphabeta module.
authors.affiliation: Department of Molecular Biology, Tokyo University of Pharmacy and Life Science, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Akanuma
authors.forename: Hiroh
authors.initials: H
authors.lastname: Miyagawa
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Kitamura
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yamagishi
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000737:chemistry*; D003198:Computer Simulation; D003201:Computers; D004926:Escherichia coli / Q000201:enzymology*; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012984:Software; D013696:Temperature; D013816:Thermodynamics
chemical_list: D019747:Aldose-Ketose Isomerases; C029865:phosphoribosylanthranilate isomerase