Helicity of hydrophobic peptides in polar vs. non-polar environments

Abstract

The helical contents of a series of designed Ala-based host–guest hydrophobic peptides (where the guest residues include the 20 commonly occurring amino acids) were determined in both polar (aqueous solution) and non-polar (n-butanol) environments using circular dichroism spectroscopy. While the relative helicities of these peptides in water (P_polar) agree well with the helical propensity predicted by Chou and Fasman (Annu. Rev. Biochem., 1978, 47, 251) for globular proteins, their helicities in n-butanol (P_non-polar) correlate loosely with the relative hydrophobicities of the peptides as determined by HPLC retention times. To determine the relevance of helical propensity demonstrated in these model peptides to membrane proteins, we analyzed a database of 5444 transmembrane (TM) segments and 4196 non-TM helices. The amino acid frequency of the non-TM segments is correlated (71%) with P_polar, while the amino acid frequency of the TM segments is correlated (85%) with P_non-polar. Further, when mean residue helicity is computed for TM and non-TM helices of comparable length using P_polar and P_non-polar, we found that the TM segments have 64% overlap with the non-TM helices in terms of polar helicity, but only 17% overlap in terms of non-polar helicity. The results suggest that despite the necessity to fulfill the requirement of hydrophobicity by using bulky side chains and aromatic residues, the TM segment nevertheless must maintain a relatively high level of helicity in order to assume a stable helical conformation in the membrane.