Molecular modeling of the antigen-antibody complex to the investigation of autoimmune demyelinating diseases

Author(s)

Jéssica Cristiane Magalhães Ierich

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Medicina Tropical de São Paulo (IMT)
• Defense date: 2018-12-18

Examining board members

Fabio de Lima Leite; Kaline Rabelo Coutinho; Renan Barros Domingues; Thelma Suely Okay

• Advisor: Fabio de Lima Leite; Doralina Guimarães Brum Souza

Abstract

Intermolecular recognition and interaction are crucial in autoimmune demyelinating diseases pathogenesis as multiple sclerosis (MS). MS causes demyelination and axonopathy in the central nervous system (CNS). The targets of immune cells and autoantibodies are not clear, but myelin proteins, such as myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP), are potential candidates. Thus, methods of molecular modeling, molecular dynamics (MD), and steered molecular dynamics (SMD) simulation were applied to detail the recognition and binding of MOG external domain and the immunogenic MBP85-99 peptide by specific antibodies. A computational protocol based on mutations of complement determinant regions (CDR) in template structures was proposed to obtain antibodies 3D structures, especially the anti-MBP. The obtained data evidenced a significant contribution of hydrogen bonds in the maintenance of antigen-antibody complexes. Thirteen anchor residues were found in the MOG structure. These residues were related to three well-known epitopes recognized by immunologic components, mainly MOG92-106. In the case of MBP, the most interactive residues of the MBP85-99 with the anti-MBP were Arginine 99, Lysine 93, Asparagine 94, and Histidine 90. These data complied with several studies concern cellular recognition of MBP and postmortem cases involving anti-MBP. SMD information of both molecular systems was confirmed by atomic force microscopy and suggested the MOG92-106 acting as an anchor for the complex with the anti-MOG. Regarding MBP, the computational force study evidenced the importance of Arginine 99 interaction region for the antigen-antibody binding. The agreement between the obtained computational data and experimental information resulted of decades of MOG and MBP research was evident. In this context, theoretical and experimental approaches application as described here for characterizing novel molecules in autoimmune disease is a potential pathway to optimize early-stage and pre-clinical steps of investigations, guiding experiments, reducing costs, and animal model usage. (AU)

• FAPESP's process: 14/12082-4 - Molecular modeling of the antigen-antibody complex to the investigations of autoimmune demyelinating diseases
• Grantee: Jéssica Cristiane Magalhães Ierich
• Support Opportunities: Scholarships in Brazil - Doctorate