Energetics, stability, and prediction of transmembrane helices

Sajith Jayasinghe, Kalina Hristova, Stephen H. White

Research output: Contribution to journalArticlepeer-review


We show that the peptide backbone of an α-helix places a severe thermodynamic constraint on transmembrane (TM) stability. Neglect of this constraint by commonly used hydrophobicity scales underlies the notorious uncertainty of TM helix prediction by sliding-window hydropathy plots of membrane protein (MP) amino acid sequences. We find that an experiment-based whole-residue hydropathy scale (WW scale), which includes the backbone constraint, identifies TM helices of membrane proteins with an accuracy greater than 99%. Furthermore, it correctly predicts the minimum hydrophobicity required for stable single-helix TM insertion observed in Escherichia coli. In order to improve membrane protein topology prediction further, we introduce the augmented WW (aWW) scale, which accounts for the energetics of salt-bridge formation. An important issue for genomic analysis is the ability of the hydropathy plot method to distinguish membrane from soluble proteins. We find that the method falsely predicts 17 to 43% of a set of soluble proteins to be MPs, depending upon the hydropathy scale used.

Original languageEnglish (US)
Pages (from-to)927-934
Number of pages8
JournalJournal of molecular biology
Issue number5
StatePublished - Oct 5 2001
Externally publishedYes


  • Genomic analysis
  • Hydropathy plots
  • Membrane proteins
  • Peptide bond
  • Structure prediction

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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