The magnitude of the backbone conformational entropy change in protein folding

J. Alejandro D'Aquino, Javier Gómez, Vincent J. Hilser, Kon Ho Lee, Mario L Amzel, Ernesto I Freire

Research output: Contribution to journalArticle

Abstract

The magnitude of the conformational entropy change experienced by the peptide backbone upon protein folding was investigated experimentally and by computational analysis. Experimentally, two different pairs of mutants of a 33 amino acid peptide corresponding to the leucine zipper region of GCN4 were used for high-sensitivity microcalorimetric analysis. Each pair of mutants differed only by having alanine or glycine at a specific solvent-exposed position under conditions in which the differences in stability could be attributed to differences in the conformational entropy of the unfolded state. The mutants studied were characterized by different stabilities but had identical heat capacity changes of unfolding (ΔC(p)), identical solvent- related entropies of unfolding (ΔS(solv)), and identical enthalpies of unfolding (ΔH) at equivalent temperatures. Accordingly, the differences in stability between the different mutants could be attributed to differences in conformational entropy. The computational studies were aimed at generating the energy profile of backbone conformations as a function of the main chain dihedral angles φ and ψ. The energy profiles permit a direct calculation of the probability distribution of different conformers and therefore of the conformational entropy of the backbone. The experimental results presented in this paper indicate that the presence of the methyl group in alanine reduces the conformational entropy of the peptide backbone by 2.46 ± 0.2 cal/K · mol with respect to that of glycine, consistent with a 3.4-fold reduction in the number of allowed conformations in the alanine-containing peptides. Similar results were obtained from the energy profiles. The computational analysis also indicates that the addition of further carbon atoms to the side chain had only a small effect as long as the side chains were unbranched at position β. A further reduction with respect to Ala of only 0.61 and 0.81 cal/K · mol in the backbone entropy was obtained for leucine and lysine, respectively. β-branching (Val) produces the largest decrease in conformational entropy (1.92 cal/K · mol less than Ala). Finally, the backbone entropy change associated with the unfolding of an α-helix is 6.51 cal/K · mol for glycine. These and previous results have allowed a complete estimation of the conformational entropy changes associated with protein folding.

Original languageEnglish (US)
Pages (from-to)143-156
Number of pages14
JournalProteins
Volume25
Issue number2
DOIs
StatePublished - 1996

Fingerprint

Protein folding
Protein Folding
Entropy
Alanine
Glycine
Peptides
Conformations
Leucine Zippers
Dihedral angle
Leucine
Probability distributions
Lysine
Sensitivity analysis
Specific heat
Enthalpy
Carbon
Hot Temperature

ASJC Scopus subject areas

  • Genetics
  • Structural Biology
  • Biochemistry

Cite this

The magnitude of the backbone conformational entropy change in protein folding. / D'Aquino, J. Alejandro; Gómez, Javier; Hilser, Vincent J.; Lee, Kon Ho; Amzel, Mario L; Freire, Ernesto I.

In: Proteins, Vol. 25, No. 2, 1996, p. 143-156.

Research output: Contribution to journalArticle

D'Aquino, J. Alejandro ; Gómez, Javier ; Hilser, Vincent J. ; Lee, Kon Ho ; Amzel, Mario L ; Freire, Ernesto I. / The magnitude of the backbone conformational entropy change in protein folding. In: Proteins. 1996 ; Vol. 25, No. 2. pp. 143-156.
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