Modeling Sequence-Dependent Peptide Fluctuations in Immunologic Recognition

Ayres, Cory M.; Riley, Timothy P.; Corcelli, Steven A.; Baker, Brian M.

doi:10.1021/acs.jcim.7b00118

Cited by 13 publications

(23 citation statements)

References 36 publications

(89 reference statements)

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“…Recently, we described a library of extensive molecular dynamics simulations of 52 different nonameric peptides bound to the class I MHC protein HLA-A2 using available crystallographic structures for starting coordinates (34). In our previous work, we assessed how peptide composition influenced peptide motion within the HLA-A2 binding groove.…”

Section: Introductionmentioning

confidence: 99%

Dynamically Driven Allostery in MHC Proteins: Peptide-Dependent Tuning of Class I MHC Global Flexibility

et al. 2019

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T cell receptor (TCR) recognition of antigenic peptides bound and presented by class I major histocompatibility complex (MHC) proteins underlies the cytotoxic immune response to diseased cells. Crystallographic structures of TCR-peptide/MHC complexes have demonstrated how TCRs simultaneously interact with both the peptide and the MHC protein. However, it is increasingly recognized that, beyond serving as a static platform for peptide presentation, the physical properties of class I MHC proteins are tuned by different peptides in ways that are not always structurally visible. These include MHC protein motions, or dynamics, which are believed to influence interactions with a variety of MHC-binding proteins, including not only TCRs, but other activating and inhibitory receptors as well as components of the peptide loading machinery. Here, we investigated the mechanisms by which peptides tune the dynamics of the common class I MHC protein HLA-A2. By examining more than 50 lengthy molecular dynamics simulations of HLA-A2 presenting different peptides, we identified regions susceptible to dynamic tuning, including regions in the peptide binding domain as well as the distal α3 domain. Further analyses of the simulations illuminated mechanisms by which the influences of different peptides are communicated throughout the protein, and involve regions of the peptide binding groove, the β 2 -microglobulin subunit, and the α3 domain. Overall, our results demonstrate that the class I MHC protein is a highly tunable peptide sensor whose physical properties vary considerably with bound peptide. Our data provides insight into the underlying principles and suggest a role for dynamically driven allostery in the immunological function of MHC proteins.

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Section: Introductionmentioning

confidence: 99%

Dynamically Driven Allostery in MHC Proteins: Peptide-Dependent Tuning of Class I MHC Global Flexibility

et al. 2019

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“…The relationship between peptide sequence and propagation of fluctuations, as observed also in our study, is of interest when considering antigen immunogenicity. A large‐scale study with extensive sampling by Ayres et al has analyzed the fluctuations of nonameric peptides restricted by MHC class I molecules to generate a model for peptide flexibility based on peptide sequence and chemical composition.…”

Section: Resultsmentioning

confidence: 99%

“…MD simulations, despite known limitations such as accessible timescales and accuracy of the force fields, have provided significant insights in the flexibility of TCR/pMHC complexes. [8][9][10][11][12][13] Recently, Fodor and coworkers 9 applied an ensemble enrichment method, which relies on multiple short MD simulations starting from X-ray diffraction data, to study conformational changes at TCR/pMHC interfaces. They extracted information of underlying dynamics overlooked in the comparison of crystal structures of TCR-bound and unbound pMHCs.…”

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confidence: 99%

The 3A6‐TCR/superagonist/HLA‐DR2a complex shows similar interface and reduced flexibility compared to the complex with self‐peptide

2019

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T‐cell receptor (TCR) recognition of the myelin basic protein (MBP) peptide presented by major histocompatibility complex (MHC) protein HLA‐DR2a, one of the MHC class II alleles associated with multiple sclerosis, is highly variable. Interactions in the trimolecular complex between the TCR of the MBP83‐99‐specific T cell clone 3A6 with the MBP‐peptide/HLA‐DR2a (abbreviated TCR/pMHC) lead to substantially different proliferative responses when comparing the wild‐type decapeptide MBP90‐99 and a superagonist peptide, which differs mainly in the residues that point toward the TCR. Here, we investigate the influence of the peptide sequence on the interface and intrinsic plasticity of the TCR/pMHC trimolecular and pMHC bimolecular complexes by molecular dynamics simulations. The intermolecular contacts at the TCR/pMHC interface are similar for the complexes with the superagonist and the MBP self‐peptide. The orientation angle between TCR and pMHC fluctuates less in the complex with the superagonist peptide. Thus, the higher structural stability of the TCR/pMHC tripartite complex with the superagonist peptide, rather than a major difference in binding mode with respect to the self‐peptide, seems to be responsible for the stronger proliferative response.

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“…Thus, a single difference between two peptides can have effects that propagate to contacts involving residues distant in sequence and space from the mutated one. A large-scale study with extensive sampling by Ayres et al (11) has analyzed the fluctuations of nonameric peptides restricted by MHC class I molecules to generate a model for peptide flexibility based on peptide sequence and chemical composition. The relationship between peptide sequence and propagation of fluctuations, as observed also in our study, is of interest when considering antigen immunogenicity.…”

Section: Simulations Of the Pmhc Bimolecular Complexmentioning

confidence: 99%

“…MD simulations, despite known limitations such as accessible timescales and accuracy of the force fields, have provided significant insights in the flexibility of TCR/pMHC complexes (7)(8)(9)(10)(11)(12). Recently, Fodor et al (12) applied an ensemble enrichment method, which relies on multiple short MD simulations starting from X-ray diffraction data, to study conformational changes at TCR/pMHC interfaces.…”

Section: Introductionmentioning

confidence: 99%

The TCR/peptide/MHC complex with a superagonist peptide shows similar interface and reduced flexibility compared to the complex with a self-peptide

Salutari

Martin

Caflisch

2019

Preprint

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T-cell receptor (TCR) recognition of myelin basic protein (MBP) peptide presented by major histocompatibility complex (MHC) protein HLA-DR2a, one of the MHC class II alleles associated with multiple sclerosis, is highly variable. Interactions in the trimolecular complex between the TCR of MBP83-99-specific T cell clone 3A6 with the MBP-peptide/HLA-DR2a (abbreviated TCR/pMHC) lead to substantially different proliferative responses when comparing the wild-type decapeptide MBP90-99 and a superagonist peptide which differs mainly in the residues that point towards the TCR. Here we investigate the influence of the peptide sequence on the interface and intrinsic plasticity of the TCR/pMHC trimolecular and pMHC bimolecular complexes by molecular dynamics simulations. The intermolecular contacts at the TCR/pMHC interface are similar for the complexes with the superagonist and the MBP self-peptide. The orientation angle between TCR and pMHC fluctuates less in the complex with the superagonist peptide. Thus, the higher structural stability of the TCR/pMHC tripartite complex with the superagonist peptide, rather than a major difference in binding mode with respect to the self-peptide, seems to be responsible for the stronger proliferative response.

show abstract

Modeling Sequence-Dependent Peptide Fluctuations in Immunologic Recognition

Cited by 13 publications

References 36 publications

Dynamically Driven Allostery in MHC Proteins: Peptide-Dependent Tuning of Class I MHC Global Flexibility

Dynamically Driven Allostery in MHC Proteins: Peptide-Dependent Tuning of Class I MHC Global Flexibility

The 3A6‐TCR/superagonist/HLA‐DR2a complex shows similar interface and reduced flexibility compared to the complex with self‐peptide

The TCR/peptide/MHC complex with a superagonist peptide shows similar interface and reduced flexibility compared to the complex with a self-peptide

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