In an effort to understand the different biological properties of natural L and retro-inverso (RI) peptides in complex with MHC class II molecules, we analysed the molecular interaction patterns and conformational behaviour of the RI-peptides with MHC class II molecules. By homology to the crystal structure of the human leukocyte antigen DR1 (HLA-DR1) complexed with influenza haemagglutinin epitope (HA) a model for the bovine leukocyte antigen BoLA-DRB3*0201 was built. The foot and mouth disease virus (FMDV) derived peptides with strongest MHC binding and T cell proliferative capacity were selected for modelling and minimisation. The non-bonded interaction energy between MHC and ligand was slightly less in RI-complexes when compared with L complexes. However, the internal bonded energy of the RI-peptides showed considerable conformational strain. Furthermore, we postulated that the RI-peptides should be able to adopt a reversed orientation in the groove in order to mimic their natural L-counterparts. To investigate the hypothesis that, RI-peptides might prefer their secondary structure in a right handed (RH) polyproline twist, rather than the left handed (LH) polyproline type II twist, we forced them into a RH twist and analysed their interaction patterns. Interestingly, these data support our idea that, the RH conformation is the preferred conformation for RI-peptides. This however, disrupts the mimicry and abolishes most interactions with MHC. This may explain our earlier observation that, RI-peptides were not able to mimic their parent L peptides in terms of interaction with MHC class II molecules.

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