Residue patterning in helix interiorsThis paper is one of a selection of papers published in this special issue entitled “Canadian Society of Biochemistry, Molecular & Cellular Biology 52nd Annual Meeting — Protein Folding: Principles and Diseases” and has undergone the Journal's usual peer review process.

Abstract

The alpha-helix remains a focus of research because of its importance to protein folding and structure. Nevertheless, despite numerous empirical, computational, and theoretical studies, the fundamental structural properties governing their formation and stability are still unclear. We have examined the statistical occurrence of polar and apolar residue patterning in helical interiors in a large, non-redundant dataset, and compared these patterns with those found in other structural environments. While the familiar amphipathic distributions for both polar and apolar residues are evident, our analysis also finds significant differences between these distributions. Non-amphipathic signals can also be discerned within both distributions. Most interestingly, among various positional patterning, an analysis of immediate (i,i + 1) helical neighbours found: (i) clear neighbouring preferences, with high (low) occurrences of hydrophobics (hydrophilics) next to Gly, Pro, and short polar residues; (ii) high negative (positive) correlation between residue helical propensities and the degree of neighbouring hydrophobicity (hydrophilicity); and (iii) a preferred ordering among neighbours, implying an inherent helix directionality. Because (i,i + 1) helical pairs have limited side chain - side chain interactions, thermodynamic considerations cannot readily explain these observations, nor can evolutionary pressures that enhance tertiary interactions via amphipathicity, as this particular spacing does not segregate residues onto either the same or opposing helical faces. We suggest that the mechanism of helix formation may be partly responsible for these observations. In particular, the high negative correlation between residue helical propensities and neighbouring hydrophobicity suggests that hydrophobicity may play a more important role in helix formation than currently recognized.