Structure-based Methods for Binding Mode and Binding Affinity Prediction for Peptide-MHC Complexes

Antunes, Dinler Amaral; Abella, Jayvee R.; Devaurs, Didier; Rigo, Maurício; Kavraki, Lydia E.

doi:10.2174/1568026619666181224101744

Cited by 68 publications

(71 citation statements)

References 166 publications

(233 reference statements)

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“…To our knowledge, a similar work on TCR-peptide interaction does not yet exist. Comparing motifs between TCR and antibodyantigen motifs would shed light on mechanistic similarities and differences in antibody and TCR antigen-interaction (Antunes et al, 2018;Bradley and Thomas, 2019;Dash et al, 2017;Glanville et al, 2017;Gowthaman and Pierce, 2018;Hellman et al, 2019Hellman et al, , 2019Lanzarotti et al, 2018;Ostmeyer et al, 2019;Riley and Baker, 2018;Turner et al, 2006). Furthermore, it remains to be investigated in how far the motif-based rules uncovered here for VH-VL-antigen complexes are transferable to scFV, nanobody, and other novel antibody constructs (Henry and MacKenzie, 2018;Mitchell and Colwell, 2018).…”

Section: Discussionmentioning

confidence: 97%

A compact vocabulary of paratope-epitope interactions enables predictability of antibody-antigen binding

Akbar

Jeliazkov

Robert

et al. 2019

Preprint

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Antibody recognition of antigen relies on the specific interaction of amino acids at the paratopeepitope interface. A long-standing question in the fields of immunology and structural biology is whether paratope-epitope interaction is predictable. A fundamental premise for the predictability of paratope-epitope binding is the existence of structural units that are universally shared among antibody-antigen binding complexes. Here, we identified structural interaction motifs, which together compose a vocabulary of paratope-epitope binding that is shared among investigated antibody-antigen complexes. The vocabulary (i) is finite with less than 10 4 motifs, (ii) mediates specific and non-redundant interactions between paratope-epitope pairs, (iii) is immunity-specific (distinct from the motif vocabulary used by non-immune protein-protein interactions), and (iv) enables the machine learning prediction of paratope or epitope. The discovery of a vocabulary of paratope-epitope interaction demonstrates the learnability and predictability of paratope-epitope interaction.

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Section: Discussionmentioning

confidence: 97%

A compact vocabulary of paratope-epitope interactions enables predictability of antibody-antigen binding

Akbar

Jeliazkov

Robert

et al. 2019

Preprint

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“…Structure-based predictions are another option that can improve the state of the art in the context of neoantigen discovery [ 61 , 162 ]. While the genomics-based approach utilizes sequence-based methods, the structure-based prediction is additionally capable of uncovering the significance of peptide structure and physicochemical properties, as well as the importance of post-translational modifications, such as phosphorylation [ 163 ], citrullination [ 164 ], and glycosylation [ 165 ], for peptide binding to the MHC and the TCR.…”

Section: Structure-based Approachesmentioning

confidence: 99%

Main Strategies for the Identification of Neoantigens

Gopanenko

Кособокова

Косоруков

2020

Cancers

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Genetic instability of tumors leads to the appearance of numerous tumor-specific somatic mutations that could potentially result in the production of mutated peptides that are presented on the cell surface by the MHC molecules. Peptides of this kind are commonly called neoantigens. Their presence on the cell surface specifically distinguishes tumors from healthy tissues. This feature makes neoantigens a promising target for immunotherapy. The rapid evolution of high-throughput genomics and proteomics makes it possible to implement these techniques in clinical practice. In particular, they provide useful tools for the investigation of neoantigens. The most valuable genomic approach to this problem is whole-exome sequencing coupled with RNA-seq. High-throughput mass-spectrometry is another option for direct identification of MHC-bound peptides, which is capable of revealing the entire MHC-bound peptidome. Finally, structure-based predictions could significantly improve the understanding of physicochemical and structural features that affect the immunogenicity of peptides. The development of pipelines combining such tools could improve the accuracy of the peptide selection process and decrease the required time. Here we present a review of the main existing approaches to investigating the neoantigens and suggest a possible ideal pipeline that takes into account all modern trends in the context of neoantigen discovery.

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“…Modification of native peptides alters the way peptides interact with TCR and, therefore, influences subsequent T cell activation and T cell fate. Increasing knowledge of both MHC binding registers and TCR interacting residues of peptides allowed the development of altered peptide ligands (APL), with the aim of favoring the expansion and/or induction of Tregs upon peptide recognition [reviewed in ( 72 , 73 )]. Following studies in murine disease models, showing that specific APLs were capable of eliciting cytokine release and affecting T cell polarization ( 74 , 75 ), APLs were tested in vivo in autoimmune diseases.…”

Section: Cell Free Strategiesmentioning

confidence: 99%

Induction of Antigen-Specific Tolerance in T Cell Mediated Diseases

Passerini

Gregori

2020

Front. Immunol.

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The development of novel approaches to control unwanted immune responses represents an ambitious goal in the management of a number of clinical conditions, including autoimmunity, autoinflammatory diseases, allergies and replacement therapies, in which the T cell response to self or non-harmful antigens threatens the physiological function of tissues and organs. Current treatments for these conditions rely on the use of non-specific immunosuppressive agents and supportive therapies, which may efficiently dampen inflammation and compensate for organ dysfunction, but they require lifelong treatments not devoid of side effects. These limitations induced researchers to undertake the development of definitive and specific solutions to these disorders: the underlying principle of the novel approaches relies on the idea that empowering the tolerogenic arm of the immune system would restore the immune homeostasis and control the disease. Researchers effort resulted in the development of cell-free strategies, including gene vaccination, protein-based approaches and nanoparticles, and an increasing number of clinical trials tested the ability of adoptive transfer of regulatory cells, including T and myeloid cells. Here we will provide an overview of the most promising approaches currently under development, and we will discuss their potential advantages and limitations. The field is teaching us that the success of these strategies depends primarily on our ability to dampen antigen-specific responses without impairing protective immunity, and to manipulate directly or indirectly the immunomodulatory properties of antigen presenting cells, the ultimate in vivo mediators of tolerance.

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Structure-based Methods for Binding Mode and Binding Affinity Prediction for Peptide-MHC Complexes

Cited by 68 publications

References 166 publications

A compact vocabulary of paratope-epitope interactions enables predictability of antibody-antigen binding

A compact vocabulary of paratope-epitope interactions enables predictability of antibody-antigen binding

Main Strategies for the Identification of Neoantigens

Induction of Antigen-Specific Tolerance in T Cell Mediated Diseases

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