Strong conformational propensities enhance T cell antigenicity.

Abstract The ability to predict T cell antigenic peptides would have important implications for the development of artificial vaccines. As a first step towards prediction, this report uses a new statistical technique to discover and evaluate peptide properties correlating with T cell antigenicity. This technique employs Monte Carlo computer experiments and is applicable to many problems involving protein or DNA. The technique is used to evaluate the contribution of various peptide properties to helper T cell antigenicity. The properties investigated include amphipathicities (alpha and beta), conformational propensities (alpha, beta, turn and coil), and the correlates of alpha-helices, such as the absence of helix-breakers and the positioning of the residues which stabilize alpha-helical dipoles. We also investigate segmental amphipathicity. (A peptide has this property when it contains at least two disjoint subpeptides, one hydrophobic, one hydrophilic.) Statistical correlations and stratifications assessed independent contributions to T cell antigenicity. The findings presented here have important implications for the manufacture of peptide vaccines. These implications are as follows: if possible, peptide vaccines should probably be those protein segments which have a propensity to form amphipathic alpha-helices, which do not have regions with a propensity to coil conformations, and which have a lysine at their COOH-terminus. The last two observations are of particular use in manufacturing peptides vaccines: they indicate where the synthetic peptides should be terminated. These implications are supported by the findings given below. The significances (p values) support the following statistical generalites about antigenic conformations: most helper T cell antigenic sites are amphipathic alpha-helices; alpha-helical amphipathicity and propensity to an alpha-helical conformation contribute independently to T cell antigenicity; there is evidence that some T cell antigenic sites are beta conformations instead of alpha-helices; T cell antigenic sites avoid random coiled conformations; and T cell antigenic sites are usually not segmentally amphipathic. alpha-Helical amphipathicity was significant, but segmental amphipathicity was not. This has implications for the dimensions of the structure interacting with the hydrophobic portion of an amphipathic T cell antigenic site. Lysines are unusually frequent at the COOH-terminal of T cell antigenic sites, even after accounting for tryptic digests. These lysines can stabilize alpha-helical peptides by a favorable interaction with alpha-helical dipoles. This interaction, which occurs with other charged residues and not juslty sine, is probably stronger in peptides than in native proteins because of the terminal backbone charges in free peptides. This stabilization may explain why alteration of COOH-terminal lysines often destroys antigenic activity: this experimental fact, never before noted as a general observation, is predicted by our theory. Our statistics are consistent with a "conformational hypothesis": helper T cell immunodominant sites tend b teo p eptides with strong conformational propensities that stabilize under hydrophobic interaction with some structure on the antigen-presenting cell, possiblya class I1 major histocompatibility complex protein. Thec onformational hypothesis is an extension of the amphipathicity hypothesis, which does not consider conformational propensities. Because small peptides do not commonly take stable conformations, our results support the quite reasonable notion that immunodominant sites are often those peptides most able to present the T cells with a consistent conformational picture. The studies presented here detect several properties of the amino acid sequences of antigenic peptides which correlate with helper T cell immunodominance. These properties suggest fundamental chemical rules governing T cell recognition of antigens. In addition, these properties would be valuable for incorporation into the rational design of any synthetic vaccine.