Recognition mechanisms of multiple sclerosis antibody MS with antigens EBNA1 and GlialCAM by molecular dynamics simulations

Abstract

Multiple sclerosis (MS), a severe autoimmune disease of the central nervous system (CNS), is marked by detrimental demyelination and axonal destruction. High-affinity molecular mimicry exists between Epstein-Barr virus nuclear antigen 1 (EBNA1) and glial cell adhesion molecule (GlialCAM) in CNS, leading to cross-reactivity of the cerebrospinal fluid B cell-encoded monoclonal antibody (mAb) MS39p2w174 with EBNA1 and GlialCAM. We aim to explore two interesting questions using molecular dynamics simulations in explicit solvent: how does molecular mimicry between the two antigens (Ags) contribute to the cross-reactivity of immune response? What conformational changes occur in the complementarity-determining regions (CDRs) of the mAb upon binding? Remarkably, both Ags are inclined to obey the combination of the induced-fit and the conformational-selection mechanisms by local and global structures analysis and Kolmogorov-Smirnov test, allowing the similar epitopes to be recognized by the same Ab. Conformational characterization suggests the CDR1 loop of mAb light-chain (CDR-L1) experiences significant changes. Binding-energy prediction proves the hydrogen bonds are critical for complex stability, both CDR-L1 and CDR-H3 (heavy-chain CDR3 loop) are important interaction interfaces. The role of CDR-H3 has been verified by previous studies. Furthermore, the distinct characteristics of the bindings of two Ags and Ab are demonstrated. EBNA1 shows higher binding affinity, allowing a precise fit and greater complex stability. In contrast, Glial-CAM undergoes more significant local conformational changes to achieve structural complementarity, compensating for its lower intrinsic affinity. These differences highlight varied molecular recognition strategies underlying antibody specificity and cross-reactivity. The findings provide the deep understanding for the molecular pathogenesis of MS causing by different Ags with high-affinity molecular mimicry, which provide theoretical support for further research.