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 natura lly occurring amino acids. These propensities are derived from three d ifferent experimental systems: small synthetic peptides, coiled-coil d imers, and real proteins. Thermodynamic analyses show that propensitie s from the different sets should be perfectly correlated if (1) the he lix in a protein is formed when and only when the protein is folded (t ight-coupling); and (2) the amino acid side-chains are not involved in tertiary interactions. A simple thermodynamic model is proposed in or der to understand those systems that fail (1). The model incorporates fluctuations in both native and unfolded states of the protein. Measur ements on hydrogen-exchange rate from proteins also question the valid ity of (2). A complementary model that assumes a cooperation between h elix formation and tertiary structures through side-chain interactions can explain the correlation between data from the peptides and protei ns. One possible source of this side-chain tertiary interaction is the amphiphilicity of helices in proteins. Our model is consistent with t he ideas of ''minimal frustration'' and ''protein malleability''; it e xhibits entropy-enthalpy compensation, and suggests that local unfoldi ng 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 i ts manifestations in protein helix stability is also discussed. (C) 19 96 Academic Press Limited