Molecular dynamics at the receptor level of immunodominant myelin basic protein epitope 87–99 implicated in multiple sclerosis and its antagonists altered peptide ligands: Triggering of immune response

Mantzourani, Efi; Platts, James Alexis; Brancale, Andrea; Mavromoustakos, Thomas; Tselios, Theodore

doi:10.1016/j.jmgm.2007.02.004

Cited by 25 publications

(31 citation statements)

References 58 publications

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“…Studies based on the identification of potentially immunogenic epitopes of hirudin obtained from medicinal Leech, through rational design, have not only proven to be a promising strategy for safer protein development but have also have aided in the development and improvement of computer programs capable of generating accurate and reliable data [7,11,21]. Hirudin has intrinsic factors contributing to antibody formation.…”

Section: Discussionmentioning

confidence: 99%

“…[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] ) and their mutants were built and validated by molecular modeling tools, and the RMSD values of modeled epitopes equaled 0.02 Å, In addition, the stereo chemical quality was analyzed by Ramachandran plot, which determines the distribution of the Ψ and Φ angle of the main chain. Ramachandran plot of the best epitopes model and their mutants indicated that all residues were located in the favored region.…”

Section: Discussionmentioning

confidence: 99%

“…The construction of the three-dimensional structures of the two selected epitopes (epitopes 1-15 and 13-27) ] Hir [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] ) was performed using comparative modeling, which is a technique that is used to construct three-dimensional protein structures based on structurally similar proteins that have an evolutionary relationship . The Modeller9v13 [13] program was used to construct the threedimensional structures of the epitopes using a structural alignment between the target sequence and the region of similarity of the protein template (PDB code: 4HTC) [14].…”

Section: Molecular Modeling Methodsmentioning

confidence: 99%

“…Furthermore, using the IEDB program, and based on in silico mutation of the peptide, mutated epitopes with less antigenicity were determined. ] Hir [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] were selected for further study.…”

Section: Epitope Predictionsmentioning

confidence: 99%

See 3 more Smart Citations

Structural and Dynamic Insight into Hirudin Epitopes-HLADRB1 0101 Complexes and their Modified Peptide Ligands: A Molecular Dynamic Simulation Study

Asgari¹,

Mirzahoseini

Karimipoor³

2016

Trop. J. Pharm Res

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Molecular Modeling Methodsmentioning

confidence: 99%

Section: Epitope Predictionsmentioning

confidence: 99%

See 2 more Smart Citations

Structural and Dynamic Insight into Hirudin Epitopes-HLADRB1 0101 Complexes and their Modified Peptide Ligands: A Molecular Dynamic Simulation Study

Asgari¹,

Mirzahoseini

Karimipoor³

2016

Trop. J. Pharm Res

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“…NMR spectroscopy is coupled with MD simulations to study the binding motif of the altered peptide epitopes of MBP 83-99 with HLA-DR2 [19][20][21][22][23][24][25][26][27][28][29][30][31].…”

Section: Introductionmentioning

confidence: 99%

Conformational analysis of the ΜΒΡ83–99 (Phe91) and ΜΒΡ83–99 (Tyr91) peptide analogues and study of their interactions with the HLA-DR2 and human TCR receptors by using Molecular Dynamics

Potamitis

Matsoukas

Tselios

et al. 2011

J Comput Aided Mol Des

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The two new synthetic analogues of the MBP(83-99) epitope substituted at Lys(91) (primary TCR contact) with Phe [MBP(83-99) (Phe(91))] or Tyr [MBP(83-99) (Tyr(91))], have been structurally elucidated using 1D and 2D high resolution NMR studies. The conformational analysis of the two altered peptide ligands (APLs) has been performed and showed that they adopt a linear and extended conformation which is in agreement with the structural requirements of the peptides that interact with the HLA-DR2 and TCR receptors. In addition, Molecular Dynamics (MD) simulations of the two analogues in complex with HLA-DR2 (DRA, DRB1*1501) and TCR were performed. Similarities and differences of the binding motif of the two analogues were observed which provide a possible explanation of their biological activity. Their differences in the binding mode in comparison with the MBP(83-99) epitope may also explain their antagonistic versus agonistic activity. The obtained results clearly indicate that substitutions in crucial amino acids (TCR contacts) in combination with the specific conformational characteristics of the MBP(83-99) immunodominant epitope lead to an alteration of their biological activity. These results make the rational drug design intriguing since the biological activity is very sensitive to the substitution and conformation of the mutated MBP epitopes.

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Unnatural amino acids improve affinity and modulate immunogenicity: Developing peptides to treat MHC type II autoimmune disorders

2018

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Many autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (RA), and celiac disease (CD), arise from improper immune system recognition of self or benign peptides as threats. No autoimmune disease currently has a cure. Many treatments suppress the entire immune system to decrease symptom severity. The core molecular interaction underlying these diseases involves specific alleles of the human leukocyte antigen (HLA) receptor hosting the immunodominant peptides associated with the disease (i.e., myelin basic protein, Type II collagen, or α‐gliadin) in their binding groove. Once bound, circulating T‐cells can recognize the HLA‐antigen complex and initiate the complex cascade that forms an adaptive immune response. This initial HLA‐antigen interaction is a promising target for therapeutic intervention. Two general strategies have been pursued: altered peptide ligands (APLs) that attempt to recruit a different class of T‐cell to induce an anti‐inflammatory response to balance the pro‐inflammatory response associated with the antigen; and HLA‐blockers (HLABs), peptides that quantitatively displace the antigen to inhibit the immune response. Both approaches would benefit from improved HLA‐drug binding, but as the HLA receptors are highly promiscuous, the binding sites are not specific for any natural amino acid. Unnatural amino acids, either designed or screened through high‐throughput assays, may provide a solution. This review summarizes the nascent field of using noncanonical residues to treat MS, RA and CD, focusing on the importance of specific molecular interactions, and provides some examples of the synthesis of these unnatural residues.

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Molecular dynamics at the receptor level of immunodominant myelin basic protein epitope 87–99 implicated in multiple sclerosis and its antagonists altered peptide ligands: Triggering of immune response

Cited by 25 publications

References 58 publications

Structural and Dynamic Insight into Hirudin Epitopes-HLADRB1 0101 Complexes and their Modified Peptide Ligands: A Molecular Dynamic Simulation Study

Structural and Dynamic Insight into Hirudin Epitopes-HLADRB1 0101 Complexes and their Modified Peptide Ligands: A Molecular Dynamic Simulation Study

Conformational analysis of the ΜΒΡ83–99 (Phe91) and ΜΒΡ83–99 (Tyr91) peptide analogues and study of their interactions with the HLA-DR2 and human TCR receptors by using Molecular Dynamics

Unnatural amino acids improve affinity and modulate immunogenicity: Developing peptides to treat MHC type II autoimmune disorders

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