Relationship of sidechain hydrophobicity and α‐helical propensity on the stability of the single‐stranded amphipathic α‐helix

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Abstract
The aim of the present investigation is to determine the effect of α‐helical propensity and sidechain hydrophobicity on the stability of amphipathic α‐helices. Accordingly, a series of 18‐residue amphipathic α‐helical peptides has been synthesized as a model system where all 20 amino acid residues were substituted on the hydrophobic face of the amphipathic α‐helix. In these experiments, all three parameters (sidechain hydrophobicity, α‐helical propensity and helix stability) were measured on the same set of peptide analogues. For these peptide analogues that differ by only one amino acid residue, there was a 0.96 kcal/mole difference in α‐helical propensity between the most (Ala) and the least (Gly) α‐helical analogue, a 12.1‐minute difference between the most (Phe) and the least (Asp) retentive analogue on the reversed‐phase column, and a 32.3°C difference in melting temperatures between the most (Leu) and the least (Asp) stable analogue. The results show that the hydrophobicity and α‐helical propensity of an amino acid sidechain are not correlated with each other, but each contributes to the stability of the amphipathic α‐helix. More importantly, the combined effects of α‐helical propensity and sidechain hydrophobicity at a ratio of about 2:1 had optimal correlation with α‐helix stability. These results suggest that both α‐helical propensity and sidechain hydrophobicity should be taken into consideration in the design of α‐helical proteins with the desired stability.