Epitope Prediction And Molecular Dynamics Simulation Of RA Relative Target Antigens COMP And α-enolase

Rheumatoid arthritis is a systemic autoimmune disease characterized chronic erosive arthritis. Disease characterize is synovitis, and then resulted in destruction of articular cartilage and bone, joint space narrowing, and ultimately lead to joint deformity. This causes a great impact on human life. Discovery of auto-antigens and the presence of antibodies against auto-antigens of RA is the strong evidence of autoimmune theory. Among them, the abnormal self-antigen-driven immune response is considered to be the foundation of RA developing and the disease evolution. T cell and B cell mediated autoimmune responses involving multiple self proteins as auto-antigen. Such as cartilage oligomeric matrix protein, a-enolase, etc. are considered to be the target protein of RA. Immune recognition and binding between the antibody and antigen molecule occurs in specific sequence area or a specific fragment. It is very important to clarify the epitope of specific antigen for the study of the development of RA pathology and treatment of defense.This research using bioinformatics prediction combined with molecular dynamics simulation to study the epitopes of cartilage oligomeric matrix protein and human a-enolase that highly correlated with RA, and a detail research of the binding mode of COMP with MHC-II. For human α-enolase, give a T/B cell epitope prediction and cross-reactivity prediction. The main results are as follows:Bioinformatics predictions of COMP T cell epitopes indicate that:4-68aa, 526-540aa and 596-610aa are the highly binding area with HLA-DR4. Molecular modeling using HA-DR4 (PDB ID:1J8H) as model, build three COMP-DR4 complexes, they are COMP54-68-DR4, COMP526-540-DR4 and COMP596-610-DR4.The results of the modeling COMP-DR4 complexes using molecular dynamics simulation to optimize, and then using PROCHECK and ERRAT program to evaluate the structure of COMP-DR4 complexes. The results show that COMP-DR4 complexes are reasonable in conformation. PROSA calculation process show that COMP-DR4 complexes falls within the reasonable Zscore.To analyze the characteristics of COMP polypeptide binding with MHC, we conclude that antigenic polypeptide mainly connect HLA-DR4 with al chain, (31 chain and β sheet structure. The results of free energy calculating show that COMP54-68 has the highest binding affinity with HLA-DR4.Bioinformatics predictions of human a-enolase show that:27-41aa,127-141aa, 197-211aa,280-294aa and 377-391aa are the high credibility T cell epitopes region of HLA-DRB1*0401 alles. While the HLA-DRB1* 0101, HLA-DRB1* 0404 and HLA-DRB1*0405 genotype bioinformatics predictions analysis showed that 27-41aa are shared epitopes for the four genotypes, and 165-179aa is common epitope for DRB1 * 0101, DRB1* 0404 and DRB1* 0405 these three genotypes. Advantage linear B-cell epitopes regions are:28-43aa,70-85aa,122-137aa,163-178aa,229-244aa,280-295aa; Advantage conformational B cell epitope regions are:1-4/24-30/77-86/124aa, 9-16/51-59aa,250-254/262-268/271-274aa. By sequence analysis found that human a-enolase and Porphyromonas gingivalis enolase has a high degree of homology, and has the same sequence at linear B-cell epitope regions. Homology modeling Porphyromonas gingivalis enolase using Streptococcus pneumoniae plasminogen binding a-enolase (PDB ID:1w6t) as template. The modeling three-dimensional structure and human a-enolase through conformation blast show that the RMSD is 1.055A, which indicate that the conformation of them are very the same, and a high probability of cross-reactivity between them.