Dataset Information

Design of Linear and Cyclic Mutant Analogues of Dirucotide Peptide (MBP82?98) against Multiple Sclerosis: Conformational and Binding Studies to MHC Class II.

ABSTRACT: BACKGROUND:Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system. MS is a T cell-mediated disease characterized by the proliferation, infiltration, and attack of the myelin sheath by immune cells. Previous studies have shown that cyclization provides molecules with strict conformation that could modulate the immune system. METHODS:In this study, we synthesized peptide analogues derived from the myelin basic protein (MBP)82?98 encephalitogenic sequence (dirucotide), the linear altered peptide ligand MBP82?98 (Ala91), and their cyclic counterparts. RESULTS:The synthesized peptides were evaluated for their binding to human leukocyte antigen (HLA)-DR2 and HLA-DR4 alleles, with cyclic MBP82?98 being a strong binder with the HLA-DR2 allele and having lower affinity binding to the HLA-DR4 allele. In a further step, conformational analyses were performed using NMR spectroscopy in solution to describe the conformational space occupied by the functional amino acids of both linear and cyclic peptide analogues. This structural data, in combination with crystallographic data, were used to study the molecular basis of their interaction with HLA-DR2 and HLA-DR4 alleles. CONCLUSION:The cyclic and APL analogues of dirucotide are promising leads that should be further evaluated for their ability to alter T cell responses for therapeutic benefit against MS.

SUBMITTER: Deraos G

PROVIDER: S-EPMC6316436 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Design of Linear and Cyclic Mutant Analogues of Dirucotide Peptide (MBP<sub>82⁻98</sub>) against Multiple Sclerosis: Conformational and Binding Studies to MHC Class II.

Deraos George G Kritsi Eftichia E Matsoukas Minos-Timotheos MT Christopoulou Konstantina K Kalbacher Hubert H Zoumpoulakis Panagiotis P Apostolopoulos Vasso V Matsoukas John J

Brain sciences 20181204 12

<h4>Background</h4>Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system. MS is a T cell-mediated disease characterized by the proliferation, infiltration, and attack of the myelin sheath by immune cells. Previous studies have shown that cyclization provides molecules with strict conformation that could modulate the immune system.<h4>Methods</h4>In this study, we synthesized peptide analogues derived from the myelin basic protein (MBP)<sub>82⁻98</sub> encephalitogenic s ...[more]

PMID: 30518150

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Project description:Major Histocompatibility Complex (MHC) class I molecules enable cytotoxic T lymphocytes to destroy virus-infected or cancerous cells, thereby preventing disease progression. MHC class I molecules provide a snapshot of the contents of a cell by binding to protein fragments arising from intracellular protein turnover and presenting these fragments at the cell surface. Competing fragments (peptides) are selected for cell-surface presentation on the basis of their ability to form a stable complex with MHC class I, by a process known as peptide optimization. A better understanding of the optimization process is important for our understanding of immunodominance, the predominance of some T lymphocyte specificities over others, which can determine the efficacy of an immune response, the danger of immune evasion, and the success of vaccination strategies. In this paper we present a dynamical systems model of peptide optimization by MHC class I. We incorporate the chaperone molecule tapasin, which has been shown to enhance peptide optimization to different extents for different MHC class I alleles. Using a combination of published and novel experimental data to parameterize the model, we arrive at a relation of peptide filtering, which quantifies peptide optimization as a function of peptide supply and peptide unbinding rates. From this relation, we find that tapasin enhances peptide unbinding to improve peptide optimization without significantly delaying the transit of MHC to the cell surface, and differences in peptide optimization across MHC class I alleles can be explained by allele-specific differences in peptide binding. Importantly, our filtering relation may be used to dynamically predict the cell surface abundance of any number of competing peptides by MHC class I alleles, providing a quantitative basis to investigate viral infection or disease at the cellular level. We exemplify this by simulating optimization of the distribution of peptides derived from Human Immunodeficiency Virus Gag-Pol polyprotein.

Project description:Major histocompatibility complex class I proteins play a key role in the recognition and presentation of peptide antigens to the host immune system. The structure of various major histocompatibility complex class I proteins has been determined experimentally in complex with several antigenic peptides. However, the structure in the unbound (empty) form is not known. To study the conformational dynamics of the empty major histocompatibility complex class I molecule comparative molecular dynamics simulations have been performed starting from the crystal structure of a peptide bound class I peptide-binding domain in the presence and absence of a peptide ligand. Simulations including the bound peptide stayed close to the experimental start structure at both simulation temperatures (300 and 355 K) during the entire simulation of 26 ns. Several independent simulations in the absence of peptide indicate that the empty domain may not adopt a single defined conformation but is conformationally significantly more heterogeneous in particular within the alpha-helices that flank the peptide binding cleft. The calculated conformational dynamics along the protein chain correlate well with available spectroscopic data and with the observed site-specific sensitivity of the empty class I protein to proteolytic digestion. During the simulations at 300 K the binding region for the peptide N-terminus stayed close to the conformation in the bound state, whereas the anchor region for the C-terminus showed significantly larger conformational fluctuations. This included a segment at the beginning of the second alpha-helix in the domain that is likely to be involved in the interaction with the chaperone protein tapasin during the peptide-loading process. The simulation studies further indicate that peptide binding at the C- and N-terminus may follow different mechanisms that involve different degrees of induced conformational changes in the peptide-binding domain. In particular binding of the peptide C-terminus may require conformational stabilization by chaperone proteins during peptide loading.

Dataset Information

Design of Linear and Cyclic Mutant Analogues of Dirucotide Peptide (MBP82?98) against Multiple Sclerosis: Conformational and Binding Studies to MHC Class II.

Publications

Design of Linear and Cyclic Mutant Analogues of Dirucotide Peptide (MBP<sub>82⁻98</sub>) against Multiple Sclerosis: Conformational and Binding Studies to MHC Class II.

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