Hydrophobic strip-of-helix algorithm for selection of T cell-presented peptides

In extension of the hypothesis that an amphipathic alpha helix of I_i (Phe₁₄₆-Val₁₆₄) bound to the foreign antigen-presenting site (desetope) of class II MHC molecules through hydrophobic amino acid residues (Phe₁₄₆, Leu₁₅₀, Leu₁₅₃, Met₁₅₇, Ile₁₆₀, Val₁₆₄) which were present in an axial strip along one side of the I_i helix, we developed an algorithm to search for T cell-presented peptides showing a similar hydrophobic strip-of-helix. Such peptides might bind to the class II MHC molecule site which was complementary to the I_i hydrophobic strip-of-helix. The strip-of-helix hydrophobicity index was the mean hydrophobicity (from Kyte-Doolittle values) of sets of amino acids in axial strips down sides of helices for 3-6 turns, at positions, n, n + 4, n + 7, n + 11, n + 14, and n + 18. Peptides correlating well with T cell responsiveness had: (1) 12-19 amino acids (3-5 cycles or 4-6 turns of an alpha helix), (2) a strip with highly hydrophobic residues, (3) adjacent, moderately hydrophilic strips, and (4) no prolines. The degree of hydrophilicity of the remainder of a putative antigenic helix above a threshold value did not count in this index. That is, the magnitude of amphipathicity was not judged to be the principal selecting factor for T cell-presented peptides. This simple algorithm to quantitate strip-of-helix hydrophobicity in a putative amphipathic alpha helix, allowing otherwise generally hydrophilic residues, predicted 10 of 12 T cell-presented peptides in seven well-studied proteins. The derivation and application of this algorithm were analyzed.