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

Scientific Reports
Agostino BrunoVittorio Limongelli

Abstract

Glycoproteins are often recognized as not-self molecules by antibodies triggering the onset of severe autoimmune diseases such as Multiple Sclerosis (MS). Thus, the development of antigen-mimicking biomarkers represents an attractive strategy for an early diagnosis of the disease. An example is the synthetic glycopeptide CSF114(Glc), which was designed and tested as MS biomarker and whose clinical application was limited by its reduced ability to detect autoantibodies in MS patients. In the attempt to improve the efficacy of CSF114(Glc), we have characterized all the events leading to the final binding of the biomarker to the autoantibody using atomistic simulations, ESR and NMR experiments. The glycosydic moiety plays a primary role in the whole process. In particular, in an environment mimicking that used in the clinical tests the glycopeptide assumes a α-helix structure that is functional for the interaction with the antibody. In this conformation CSF114(Glc) binds the monoclonal antibody mAb8-18C5 similarly to the myelin oligodendrocyte glycoprotein MOG, which is a known MS auto-antigen, thus explaining its diagnostic activity. Our study offers new molecular bases to design more effective biomarkers and provides a most vali...Continue Reading

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Citations

May 27, 2016·Journal of Chemical Theory and Computation·Federico ComitaniCarla Molteni
Feb 14, 2017·The Journal of Physical Chemistry Letters·Anirban PolleyIlpo Vattulainen
Feb 25, 2017·Proceedings of the National Academy of Sciences of the United States of America·Federica MoracaVittorio Limongelli
Nov 5, 2019·Frontiers in Bioengineering and Biotechnology·Tommaso CasaliniGiuseppe Perale
Nov 16, 2019·Journal of Peptide Science : an Official Publication of the European Peptide Society·Jaideep SinghCory L Brooks
Feb 27, 2018·Journal of Chemical Information and Modeling·Joana MagalhãesGabriele Costantino
Dec 13, 2018·Journal of Chemical Theory and Computation·Z Faidon BrotzakisMichele Parrinello

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Methods Mentioned

BETA
NMR
ESR
X-ray

Software Mentioned

Macromodel
NAMD
Amber11
Insight
SPARKY
Maestro9
MATLAB
vmd
ptraj
CYANA

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