Possible locally driven folding pathways of TC5b, a 20-residue protein

Gregory V. Nikiforovich, Niels H. Andersen, R. Matthew Fesinmeyer, Carl Frieden

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26 Scopus citations


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 mini-protein. 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 α-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 Trp6-Pro12, then Trp6-Pro18, and then Trp6-Tyr3. 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.

Original languageEnglish
Pages (from-to)292-302
Number of pages11
JournalProteins: Structure, Function and Genetics
Issue number2
StatePublished - Aug 1 2003


  • Local interactions
  • Miniprotein
  • Peptides
  • Stepwise elongation


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