Locating the Stabilizing Residues in (α/β)8 Barrel Proteins Based on Hydrophobicity, Long-Range Interactions, and Sequence Conservation

M. Michael Gromiha, Gerard Pujadas, Csaba Magyar, Samuel Selvaraj, Istvan Simon

Research output: Contribution to journalArticle

73 Citations (Scopus)


In nature, 1 out of every 10 proteins has an (α/β)8 (TIM)-barrel fold, and in most cases, pairwise comparisons show no sequence similarity between them. Hence, delineating the key residues that induce very different sequences to share a common fold is important for understanding the folding and stability of TIM-barrel domains. In this work, we propose a new consensus approach for locating these stabilizing residues based on long-range interactions, hydrophobicity, and conservation of amino acid residues. We have identified 957 stabilizing residues in 63 proteins from a nonredundant set of 71 TIM-barrel domains. Most of these residues are located in the 8-stranded β-sheet, with nearly one half of them oriented toward the interior of the barrel and the other half oriented toward the surrounding α-helices. Several stabilizing residues are found in the N- and C-terminal loops, whereas very few appear in the α-helices that surround the internal β-sheet. Further, these 957 residues are placed in 434 stabilizing segments of various sizes, and each domain contains 1-10 of these segments. We found that 8 segments per domain is the most abundant one, and two thirds of the proteins have 7-9 stabilizing segments. Finally, we verified the identified residues with experimental temperature factors and found that these residues are among the ones with less mobility in the considered proteins. We suggest that our new protocol serves as a powerful tool to identify the stabilizing residues in TIM-barrel domains, which can be used as potential candidates for studying protein folding and stability by means of protein engineering experiments.

Original languageEnglish
Pages (from-to)316-329
Number of pages14
JournalProteins: Structure, Function and Genetics
Issue number2
Publication statusPublished - May 1 2004


  • Conservation
  • Long-range order
  • Stabilization center
  • Surrounding hydrophobicity
  • TIM barrel
  • Temperature factor

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology

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