Predicting antigenic determinants in proteins: looking for unidimensional solutions to a three-dimensional problem?

In a recent review, Hopp (Peptide Research 6:183-190, 1993) claimed that the Hopp and Woods hydrophilicity method for locating antigenic determinants is superior to all other existing methods for predicting the B cell epitopes of proteins but that it is not useful to aid the investigator in producing peptide-protein cross-reactive antisera. In this article, we challenge both these assertions. Most investigators utilize antigenicity prediction algorithms because they wish to produce anti-peptide antibodies capable of cross-reacting with the intact protein. All prediction methods are based on propensity scales for the 20 amino acids, which describe the tendency of each residue to be associated with properties such as hydrophilicity, surface accessibility or segmental mobility. When we compared the prediction efficacy of 22 different scales, taking into account both correct and incorrect predictions, we found that none of the scales gave a level of correct prediction higher than about 50%-60%. If no antigenicity was found in a particular region of the protein, we took the view that hydrophilicity peaks located in that region amounted to wrong predictions. The much higher success rate reported by Hopp for this method stems from the way he assesses prediction efficacy, i.e., by counting the number of known epitopes located inside and outside hydrophilicity peaks. Reasons for the low success rate of antigenicity prediction are discussed. In most cases, it is unrealistic to try to reduce the complexity of discontinuous, conformational epitopes to simple, linear peptide models.