Interactions between a helical residue and tertiary structures: helix propensities in small peptides and in native proteins.

We compare three complete sets of helix propensities for the 20 naturally occurring amino acids. These propensities are derived from three different experimental systems: small synthetic peptides, coiled-coil dimers, and real proteins. Thermodynamic analyses show that propensities from the different sets should be perfectly correlated if (1) the helix in a protein is formed when and only when the protein is folded (tight-coupling); and (2) the amino acid side-chains are not involved in tertiary interactions. A simple thermodynamic model is proposed in order to understand those systems that fail (1). The model incorporates fluctuations in both native and unfolded states of the protein. Measurements on hydrogen-exchange rate from proteins also question the validity of (2). A complementary model that assumes a cooperation between helix formation and tertiary structures through side-chain interactions can explain the correlation between data from the peptides and proteins. One possible source of this side-chain tertiary interaction is the amphiphilicity of helices in proteins. Our model is consistent with the ideas of "minimal frustration" and "protein malleability"; it exhibits entropy-enthalpy compensation, and suggests that local unfolding and solvent penetration are correlated in a fluctuating protein. It also suggests experiments to quantitatively verify and differentiate between the models. The electrostatic nature of hydrogen bonding and its manifestations in protein helix stability is also discussed.