title: Possible locally driven folding pathways of TC5b, a 20-residue protein.
abstract: A novel computational procedure for modeling possible locally driven folding pathways by stepwise elongations of the peptide chain was successfully applied to TC5b, a 20-residue miniprotein. Systematic exploration of the possible locally driven pathways showed that the Trp-cage structure of TC5b could be obtained by stepwise elongation starting from the noncentral local nucleation centers preexisting in the unfolded state of TC5b. The probable locally driven folding pathway starts with folding of alpha-helical fragment 4-9, followed by formation of the proper three-dimensional structure of fragment 4-12, and then 4-18. Accordingly, the Trp-cage-forming interactions emerge successively, first Trp(6)-Pro(12), then Trp(6)-Pro(18), and then Trp(6)-Tyr(3). The Trp-cage-like structures of TC5b found in this study by independent energy calculations are in excellent agreement with the NMR experimental data. The same procedure rationalizes the incomplete Trp-cage formation observed for two analogs of TC5b. Generally, the success of this novel approach is encouraging and provides some justification for the use of computational simulations of locally driven protein folding.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University, St. Louis, Missouri 63110, USA. gregory@ccb.wustl.edu
authors.forename: Gregory V
authors.initials: GV
authors.lastname: Nikiforovich
authors.forename: Niels H
authors.initials: NH
authors.lastname: Andersen
authors.forename: R Matthew
authors.initials: RM
authors.lastname: Fesinmeyer
authors.forename: Carl
authors.initials: C
authors.lastname: Frieden
mesh_terms: D000595:Amino Acid Sequence; D019295:Computational Biology; D003198:Computer Simulation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry*; D011994:Recombinant Proteins; D014364:Tryptophan / Q000737:chemistry
chemical_list: D010455:Peptides; D011506:Proteins; D011994:Recombinant Proteins; C476389:TC5b protein, synthetic; D014364:Tryptophan