The long-term objective of this project is to understand quantitatively the mechanism of alpha-helix formation by peptides in water. This means being able to predict for any peptide the amount of helix that is formed by a given amino acid sequence. The health-related significance of this work is to understand the mechanism of protein folding, which is one of the most basic problems in biomedical research. The study of alpha-helix formation represents the analysis of protein folding at its simplest and most fundamental level. Exact physico-chemical answers can be obtained to questions asked about the mechanism of folding. The main determinants of peptide helix formation are known to be the helix and N-cap propensities of the 20 amino acids and the helix-stabilizing interactions that occur between specific pairs of side chains. Rapid progress has been made recently in measuring helix and N-cap propensities of the 20 amino acids in water.
The specific aims of this proposal are as follows. First, to measure these parameters in trifluoroethanol-water mixtures, for comparison with values determined in water, to help take account of the fact that helices in proteins are half exposed to water and half buried, out of contact with water. Second, to synthesize peptides whose sequences correspond to helical regions in proteins, and to compare the predicted and observed helix contents of these peptides. Third, to measure two classes of helix- stabilizing side-chain interactions: hydrogen bonds formed by specific pairs of side chains, and hydrophobic interactions formed by various pairs of nonpolar chains.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular and Cellular Biophysics Study Section (BBCA)
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Stanford University
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Baldwin, R L; Rose, G D (1999) Is protein folding hierarchic? I. Local structure and peptide folding. Trends Biochem Sci 24:26-33
Huyghues-Despointes, B M; Baldwin, R L (1997) Ion-pair and charged hydrogen-bond interactions between histidine and aspartate in a peptide helix. Biochemistry 36:1965-70
Luo, P; Baldwin, R L (1997) Mechanism of helix induction by trifluoroethanol: a framework for extrapolating the helix-forming properties of peptides from trifluoroethanol/water mixtures back to water. Biochemistry 36:8413-21
Rohl, C A; Baldwin, R L (1997) Comparison of NH exchange and circular dichroism as techniques for measuring the parameters of the helix-coil transition in peptides. Biochemistry 36:8435-42
Rohl, C A; Chakrabartty, A; Baldwin, R L (1996) Helix propagation and N-cap propensities of the amino acids measured in alanine-based peptides in 40 volume percent trifluoroethanol. Protein Sci 5:2623-37
Padmanabhan, S; York, E J; Stewart, J M et al. (1996) Helix propensities of basic amino acids increase with the length of the side-chain. J Mol Biol 257:726-34
Doig, A J; Baldwin, R L (1995) N- and C-capping preferences for all 20 amino acids in alpha-helical peptides. Protein Sci 4:1325-36
Baldwin, R L (1995) Alpha-helix formation by peptides of defined sequence. Biophys Chem 55:127-35
Scholtz, J M; Barrick, D; York, E J et al. (1995) Urea unfolding of peptide helices as a model for interpreting protein unfolding. Proc Natl Acad Sci U S A 92:185-9
Huyghues-Despointes, B M; Klingler, T M; Baldwin, R L (1995) Measuring the strength of side-chain hydrogen bonds in peptide helices: the Gln.Asp (i, i + 4) interaction. Biochemistry 34:13267-71

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