The glycan role in the glycopeptide immunogenicity revealed by atomistic simulations and spectroscopic experiments on the multiple sclerosis biomarker CSF114(Glc)

Glycoproteins are often recognized as not-self molecules by antibodies triggering the onset of severeautoimmune diseases such as Multiple Sclerosis (MS). Thus, the development of antigen-mimickingbiomarkers represents an attractive strategy for an early diagnosis of the disease. An example is the syntheticglycopeptide CSF114(Glc), which was designed and tested as MS biomarker and whose clinical applicationwas limited by its reduced ability to detect autoantibodies in MS patients. In the attempt to improve theefficacy of CSF114(Glc), we have characterized all the events leading to the final binding of the biomarker tothe autoantibody using atomistic simulations, ESR and NMR experiments. The glycosydic moiety plays aprimary role in the whole process. In particular, in an environment mimicking that used in the clinical teststhe glycopeptide assumes a a-helix structure that is functional for the interaction with the antibody. In thisconformation CSF114(Glc) binds the monoclonal antibody mAb8-18C5 similarly to the myelinoligodendrocyte glycoprotein MOG, which is a known MS auto-antigen, thus explaining its diagnosticactivity. Our study offers new molecular bases to design more effective biomarkers and provides a most validprotocol to investigate other systems where the environment effect is determinant for the biological activity.