Parallel Folding Pathways in the SH3 Domain Protein

A. R. Lam, J. M. Borreguero, F. Ding, Nikolay Dokholyan, S. V. Buldyrev, H. E. Stanley, E. Shakhnovich

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Abstract

The transition-state ensemble (TSE) is the set of protein conformations with an equal probability to fold or unfold. Its characterization is crucial for an understanding of the folding process. We determined the TSE of the src-SH3 domain protein by using extensive molecular dynamics simulations of the Gō model and computing the folding probability of a generated set of TSE candidate conformations. We found that the TSE possesses a well-defined hydrophobic core with variable enveloping structures resulting from the superposition of three parallel folding pathways. The most preferred pathway agrees with the experimentally determined TSE, while the two least preferred pathways differ significantly. The knowledge of the different pathways allows us to design the interactions between amino acids that guide the protein to fold through the least preferred pathway. This particular design is akin to a circular permutation of the protein. The finding motivates the hypothesis that the different experimentally observed TSEs in homologous proteins and circular permutants may represent potentially available pathways to the wild-type protein.

Original languageEnglish (US)
Pages (from-to)1348-1360
Number of pages13
JournalJournal of Molecular Biology
Volume373
Issue number5
DOIs
StatePublished - Nov 9 2007

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All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

Cite this

Lam, A. R., Borreguero, J. M., Ding, F., Dokholyan, N., Buldyrev, S. V., Stanley, H. E., & Shakhnovich, E. (2007). Parallel Folding Pathways in the SH3 Domain Protein. Journal of Molecular Biology, 373(5), 1348-1360. https://doi.org/10.1016/j.jmb.2007.08.032