Prediction of α-Helices in Proteins with the Hydrophobic Strip-of-Helix Template and Distributions of Other Amino Acids around the Hydrophobic Strip

Upon addition of requirements for highly characteristic distributions of helix-stabilizing residues to an α-helix predictor based upon identification of a longitudinal, hydrophobic strip-of-helix pattern, maximal sensitivity and efficiency scores approached 50% levels at a high degree of stringency. The hydrophobic strip-of-helix template (□○○○□○○□○○○□○○□○○○, joined in a circle) was applied to 247 helices to maximize the strip-of-helix hydrophobicity index (SOHHI; the mean hydrophobicity of residues in □ positions). Statistically significant increases or decreases in the frequencies of certain residues are observed in some □ and ○ positions: □ in the helix (including N- and C-terminal □ in the helix): Leu, Ile, Val, Phe, and Met; first □ positions in extensions of the template to surrounding segments: not increased Leu, Ile, Val, Phe, or Met; N-terminal ○: Asp, Glu; C-terminal ○ and the first □ after the helix: His, Lys, Arg; N-terminal ○: Asn; C-terminal ○: Gln; smallest residue in longitudinal strip-of-helix: Ala or Val at crossing points between helices. An algorithm was then derived to indicate α-helices by merging predictions with templates ○○○□○○○□○○□○○ and ○○○□○○□○○○□○○, where the SOHHI ≥ 3.0 in the Kyte-Doolittle scale. Relative to the baseline prediction using only the template, more elaborate rules using combinations of other structural patterns produced more efficient (49 versus 42%, respectively) but less sensitive (32 versus 42%, respectively) predictions when the prediction was required to overlap substantially with the known helix. These maximal sensitivities and efficiencies imply that some helices may be formed in folding intermediates but are lost upon coalescence of the final form. Better predictions of protein structure from the primary sequence may require modeling of competing interactions of local structures in folding intermediates.