Mimicry of native peptide antigens by the corresponding retro-inverso analogs is dependent on their intrinsic structure and interaction propensities.

Retro-inverso (ri) analogs of model T cell and B cell epitopes were predictively designed as mimics and then assayed for activity to understand the basis of functional ri-antigenic peptide mimicry. ri versions of two MHC class I binding peptide epitopes, one from a vesicular stomatitis virus glycoprotein (VSV(p)) and another from OVA (OVAp), exhibit structural as well as functional mimicry of their native counterparts. The two ri peptides exhibit conformational plasticity and they bind to MHC class I (H-2K(b)) similar to their native counterparts both in silico and in vivo. In fact, ri-OVAp is also presented to an OVAp-specific T cell line in a mode similar to native OVAp. In contrast, the ri version of an immunodominant B cell peptide epitope from a hepatitis B virus protein, PS1, exhibits no structural or functional correlation with its native counterpart. PS1 and its ri analog do not exhibit similar conformational propensities. PS1 is less flexible relative to its ri version. These observed structure-function relationships of the ri-peptide epitopes are consistent with the differences in recognition properties between peptide-MHC vs peptide-Ab binding where, while the recognition of the epitope by MHC is pattern based, the exquisitely specific recognition of Ag by Ab arises from the high complementarity between the Ag and the binding site of the Ab. It is evident that the correlation of conformational and interaction propensities of native L-peptides and their ri counterparts depends both on their inherent structural properties and on their mode of recognition.