Design and molecular dynamic simulation of a new double-epitope tolerogenic protein as a potential vaccine for multiple sclerosis disease

Fatemeh Banisharif-Dehkordi , Mohsen Mobini-Dehkordi , Mostafa Shakhsi-Niaei, Karim Mahnam

Abstract


One of the debilitating diseases affecting the central nervous system is multiple sclerosis (MS). As there is no definitive treatment for MS, researchers have mainly consented with optimization of strategies which slows down the progression of the disease such as specific auto-antigens tolerance induction. In this regard, the aim of this study was design of a new double-epitope protective vaccine based on interleukin (IL)-16-neuroantigens fusion proteins. First, we selected highly antigenic epitopes of myelin basic protein (MBP) (aa 84-104) and myelin oligodendrocyte glycoprotein (MOG) (aa 99-107) from available literature and our bioinformatics analysis. The correct cleavage of our constructs and major histocompatibility complex class II binding affinities of cleaved epitopes were checked and evaluated using Pepcleave and IEDB servers, respectively. Then, different combination of MOG and MBP epitopes with or without fusion to C-terminal active part of IL-16 were designed as constructs. Afterward, Modeller and Gromacs softwares used for the investigation of the MBP, and MOG epitopes antigenicity in these constructs. The results of molecular dynamics simulations showed that IL-16 in MOG + linker + MBP + IL-16 construct does not interfere with final epitopes antigenicity of MOG + linker + MBP construct. To sum up, the construct with IL-16 is suggested as a new double-epitope tolerogenic vaccine for prevention and amelioration of MS in human.


Keywords


Fusion proteins; Molecular dynamic simulation; Multiple sclerosis; Neuroantigen; Tolerogenic vaccine.

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Koriem KMM. Multiple sclerosis: New insights and trends. Asian Pac J Trop Biomed. 2016;6(5):429-440.

Correale J, Farez M, Gilmore W. Vaccines for multiple sclerosis: progress to date. CNS Drugs. 2008;22(3):175-198.

Fissolo N, Montalban X, Comabella M. DNA-based vaccines for multiple sclerosis: current status and future directions. Clin Immunol. 2012;142(1):76-83.

Mannie MD, Blanchfield JL, Islam SM, Abbott DJ. Cytokine-neuroantigen fusion proteins as a new class of tolerogenic, therapeutic vaccines for the treatment of inflammatory demyelinating disease in rodent models of multiple sclerosis. Front Immunol. 2012;3:255-270.

Mannie MD, Curtis AD. Tolerogenic vaccines for Multiple Sclerosis. Hum Vaccin Immunother. 2013;9(5):1032-1038.

Mannie MD, Abbott DJ. A Fusion protein consisting of IL-16 and the encephalitogenic peptide of myelin basic protein constitutes an antigen-specific tolerogenic vaccine that inhibits experimental autoimmune encephalomyelitis. J Immunol. 2007;179(3):1458-1465.

Alcina A, Abad-Grau MM, Fedetz M, Izquierdo G, Lucas M, Fernández O, et al. Multiple sclerosis risk variant HLA-DRB1*1501 associates with high expression of DRB1 gene in different human populations. PLoS One. 2012;7(1):e29819.

Krogsgaard M, Wucherpfennig KW, Cannella B, Hansen BE, Svejgaard A, Pyrdol J, et al. Visualization of myelin basic protein (MBP) T cell epitopes in multiple sclerosis lesions using a monoclonal antibody specific for the human histocompatibility leukocyte antigen (HLA)-DR2-MBP 85-99 complex. J Exp Med. 2000;191(8):1395-1412.

Blanchfield JL, Mannie MD. A GMCSF-neuroantigen fusion protein is a potent tolerogen in experimental autoimmune encephalomyelitis (EAE) that is associated with efficient targeting of neuroantigen to APC. J Leukoc Biol. 2010;87(3):509-521.

Mannie MD, Abbott DJ, Blanchfield JL. Experimental autoimmune encephalomyelitis in Lewis rats: IFN-beta acts as a tolerogenic adjuvant for induction of neuroantigen-dependent tolerance. J Immunol. 2009;182(9):5331-5341.

Blanchfield JL, Mannie MD. A GMCSF-neuroantigen fusion protein is a potent tolerogen in experimental autoimmune encephalomyelitis (EAE) that is associated with efficient targeting of neuroantigen to APC. J Leukoc Biol. 2010;87(3):509-521.

Wucherpfennig KW, Catz I, Hausmann S, Strominger JL, Steinman L, Warren KG. Recognition of the immunodominant myelin basic protein peptide by autoantibodies and HLA-DR2-restricted T cell clones from multiple sclerosis patients. Identity of key contact residues in the B-cell and T-cell epitopes. J Clin Invest. 1997;100(5):1114-1122.

Forsthuber TG, Shive CL, Wienhold W, de Graaf K, Spack EG, Sublett R, et al. T cell epitopes of human myelin oligodendrocyte glycoprotein identified in HLA-DR4 (DRB1*0401) transgenic mice are encephalitogenic and are presented by human B cells. J Immunol. 2001;167(12):7119-7125.

Vita R, Overton JA, Greenbaum JA, Ponomarenko J, Clark JD, Cantrell JR, et al. The immune epitope database (IEDB) 3.0. Nucleic Acids Res. 2015;43(Database issue):D405-D412.

Adams HP, Koziol JA. Prediction of binding to MHC class I molecules. J Immunol Methods. 1995;185(2):181-190.

Cruikshank WW, Kornfeld H, Center DM. Interleukin-16. J Leukoc Biol. 2000;67(6):757-766.

Hoze E, Tsaban L, Maman Y, Louzoun Y. Predictor for the effect of amino acid composition on CD4+ T cell epitopes preprocessing. J Immunol Methods. 2013;391(1-2):163-173.

Payab N, Mahnam K, Shakhsi-Niaei M. Computational comparison of two new fusion proteins for multiple Sclerosis. Res Pharm Sci. 2018;13(5):394-403.

Eswar N, Webb B, Marti-Renom MA, Madhusudhan MS, Eramian D, Shen MY, et al. Comparative protein structure modeling using Modeller. Curr Protoc Bioinformatics. 2006;Chapter 5:Unit-5.6.

Hornbeck PV, Zhang B, Murray B, Kornhauser JM, Latham V, Skrzypek E. PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res. 2015;43(Database issue):D512-D520.

Lovell SC, Davis IW, Arendall WB 3rd, de Bakker PI, Word JM., Prisant MG, et al. Structure validation by Calpha geometry: phi,psi and Cbeta deviation. Proteins: Structure, Function & Genetics. 2003;50(3):437-450.

Zhang C, Walker AK, Zand R, Moscarello MA, Yan JM, Andrews PC. Myelin basic protein undergoes a broader range of modifications in mammals than in lower vertebrates. J Proteome Res. 2012;11(10):4791-4802.

Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJ. GROMACS: fast, flexible, and free. J Comput Chem. 2005;26(16):1701-1718.

Darden T, York D, Pedersen L. Particle mesh Ewald: An N log (N) method for Ewald sums in large systems. J Chem Phys. 1998;98(12):10089-10092.

Mahnam K, Hoghoughi A. In silico studies on fingolimod and cladribine binding to p53 gene and its implication in prediction of their carcinogenicity potential. MBD. 2014;1(2):105-122.

Mansourian M, Madadkar-Sobhani A, Mahnam K, Fassihi A, Saghaie L. Characterization of adenosine receptor in its native environment: insights from molecular dynamics simulations of palmitoylated/glycosylated, membrane-integrated human A(2B) adenosine receptor. J Mol Model. 2012;18(9):4309-4324.

Mansouri A, Mahnam K. Designing new surfactant peptides for binding to carbon nanotubes via computational approaches. J Mol Graph Model. 2017;74:61-72.

Polverini E, Coll EP, Tieleman DP, Harauz G. Conformational choreography of a molecular switch region in myelin basic protein-molecular dynamics shows induced folding and secondary structure type conversion upon threonyl phosphorylation in both aqueous and membrane-associated environments. Biochim Biophys Acta. 2011;1808(3):674-683.

van Oss CJ, editor. The Properties of Water and their Role in Colloidal and Biological Systems. In: Hubbard A, editor. Interface Science and Technology. Vol 16. Amsterdam: Academic Press; 2008. pp. 31-48.

Zambrano R, Jamroz M, Szczasiuk A, Pujols J, Kmiecik S, Ventura S. AGGRESCAN3D (A3D): server for prediction of aggregation properties of protein structures. Nucleic Acids Res. 2015;43(W1):W306-W313.

Grote A, Hiller K, Scheer M, Münch R, Nörtemann B, Hempel DC, et al. JCat: a novel tool to adapt codon usage of a target gene to its potential expression host. Nucleic Acids Res. 2005;33(Web Server issue):W526-W531.

Koshland DE. Application of a theory of enzyme specificity to protein synthesis. Proc Natl Acad Sci U S A. 1958;44(2):98-104.

Mannie MD, Devine JL, Clayson BA, Lewis LT, Abbott DJ. Cytokine-neuroantigen fusion proteins: new tools for modulation of myelin basic protein (MBP)-specific T cell responses in experimental autoimmune encephalomyelitis. J Immunol Methods. 2007;319(1-2):118-132.

Mannie MD, Clayson BA, Buskirk EJ, DeVine JL, Hernandez JJ, Abbott DJ. IL-2/neuroantigen fusion proteins as antigen-specific tolerogens in experimental autoimmune encephalomyelitis (EAE): correlation of T cell-mediated antigen presentation and tolerance induction. J Immunol. 2007;178(5):2835-2843.

Abbott DJ, Blanchfield JL, Martinson DA, Russell SC, Taslim N, Curtis AD, et al. Neuroantigen-specific, tolerogenic vaccines: GMCSF is a fusion partner that facilitates tolerance rather than immunity to dominant self-epitopes of myelin in murine models of experimental autoimmune encephalomyelitis (EAE). BMC Immunol. 2011;12:72-89.


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