Fragment 101−108 of Myelin Oligodendrocyte Glycoprotein: A Possible Lead Compound for Multiple Sclerosis

Multiple Sclerosis (MS) is a highly invalidating autoimmune disease of the Central Nervous System, leading to progressive paralysis and, sometimes, to premature death. One of the potential targets of the autoimmune reaction is the myelin protein MOG (Myelin Oligodendrocyte Glycoprotein). Since the 101−108 fragment of MOG plays a key role in the interaction with the MS-autoantibody 8-18C5, we performed an analysis of the equilibrium conformations of this peptide using the Replica Exchange Molecular Dynamics technique in conjunction with the Generalized Born continuum solvent model. Four variants of the peptide, stabilized by a disulfide bond, were also studied. We found that a significant fraction of the equilibrium population retains the original β-hairpin conformation, and the amount of crystal-like conformations increases in the disulfide-closed analogues. When the equilibrium structures were used in docking simulations with the 8-18C5 autoantibody, we discovered the existence of a docking funnel whose bottom is populated by stable complexes where the peptide occupies the same region of space that was occupied in the crystal. It follows that the MOG 101−108 fragment represents a promising starting point for the design of a drug capable of blocking the 8-18C5 antibody. The molecule may also be used for the development of a diagnostic assay for multiple sclerosis.