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Early relaxation dynamics in the LC 13 T cell receptor in reaction to 172 altered peptide ligands: a molecular dynamics simulation study.

Knapp B, Dorffner G, Schreiner W - PLoS ONE (2013)

Bottom Line: The interaction between the T cell receptor and the major histocompatibility complex is one of the most important events in adaptive immunology.In this study, we performed systematic molecular dynamics simulations of 172 closely related altered peptide ligands in the same T cell receptor/major histocompatibility complex system.Statistical evaluations yielded significant differences in the initial relaxation process between sets of peptides at four different immunogenicity levels.

View Article: PubMed Central - PubMed

Affiliation: Center for Medical Statistics, Informatics and Intelligent Systems, Section for Biosimulation and Bioinformatics, Medical University of Vienna, Vienna, Austria. bernhard.knapp@meduniwien.ac.at

ABSTRACT
The interaction between the T cell receptor and the major histocompatibility complex is one of the most important events in adaptive immunology. Although several different models for the activation process of the T cell via the T cell receptor have been proposed, it could not be shown that a structural mechanism, which discriminates between peptides of different immunogenicity levels, exists within the T cell receptor. In this study, we performed systematic molecular dynamics simulations of 172 closely related altered peptide ligands in the same T cell receptor/major histocompatibility complex system. Statistical evaluations yielded significant differences in the initial relaxation process between sets of peptides at four different immunogenicity levels.

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Distribution of s in 500 random permutation splits.The 95% percentile and the tested map (value of s for the true split) are indicated for the four different thresholds per method. (A) Direct-method. (B) Median-method. (C) Square-method.
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pone-0064464-g004: Distribution of s in 500 random permutation splits.The 95% percentile and the tested map (value of s for the true split) are indicated for the four different thresholds per method. (A) Direct-method. (B) Median-method. (C) Square-method.

Mentions: Following the methods described above in the methods section, we simulated the distribution of systematicity values s by creating 500 random permutation splits between the groups of TCRpMHC complexes. These distributions of the random splits are depicted as histogram in Figure 4, together with the 95% percentiles as critical values. At threshold 1 (10–5 M) and using the direct-method only 4 out of 500 random permutations yielded a higher number of hits than the true split (p = 0.008). The results for the square-method were identical. For the median-method the result is marginally better (p = 0.006). At threshold 2 (10–6 M) all 3 methods yield the true split as the one with the highest number of hits. Note that this does not necessarily mean that the true split has the most extreme differences of all possible combinations; it means that within these 500 random splits none was more extreme than the true split. At threshold 3 (10–7 M) the results for the median and square-method were about equal (p = 0.016). The direct-methods is marginally better in the discrimination (p = 0.014). At threshold 4 (10–8 M) the direct-method narrowly reaches statistical significance (p = 0.046) while the median and square-method both narrowly fail the significance level (0.050 and 0.054 respectively). This could be caused by the relatively strong imbalance of 33 versus 139 TCRpMHC complexes for this threshold. However, one could still argue that there is a strong tendency.


Early relaxation dynamics in the LC 13 T cell receptor in reaction to 172 altered peptide ligands: a molecular dynamics simulation study.

Knapp B, Dorffner G, Schreiner W - PLoS ONE (2013)

Distribution of s in 500 random permutation splits.The 95% percentile and the tested map (value of s for the true split) are indicated for the four different thresholds per method. (A) Direct-method. (B) Median-method. (C) Square-method.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3675092&req=5

pone-0064464-g004: Distribution of s in 500 random permutation splits.The 95% percentile and the tested map (value of s for the true split) are indicated for the four different thresholds per method. (A) Direct-method. (B) Median-method. (C) Square-method.
Mentions: Following the methods described above in the methods section, we simulated the distribution of systematicity values s by creating 500 random permutation splits between the groups of TCRpMHC complexes. These distributions of the random splits are depicted as histogram in Figure 4, together with the 95% percentiles as critical values. At threshold 1 (10–5 M) and using the direct-method only 4 out of 500 random permutations yielded a higher number of hits than the true split (p = 0.008). The results for the square-method were identical. For the median-method the result is marginally better (p = 0.006). At threshold 2 (10–6 M) all 3 methods yield the true split as the one with the highest number of hits. Note that this does not necessarily mean that the true split has the most extreme differences of all possible combinations; it means that within these 500 random splits none was more extreme than the true split. At threshold 3 (10–7 M) the results for the median and square-method were about equal (p = 0.016). The direct-methods is marginally better in the discrimination (p = 0.014). At threshold 4 (10–8 M) the direct-method narrowly reaches statistical significance (p = 0.046) while the median and square-method both narrowly fail the significance level (0.050 and 0.054 respectively). This could be caused by the relatively strong imbalance of 33 versus 139 TCRpMHC complexes for this threshold. However, one could still argue that there is a strong tendency.

Bottom Line: The interaction between the T cell receptor and the major histocompatibility complex is one of the most important events in adaptive immunology.In this study, we performed systematic molecular dynamics simulations of 172 closely related altered peptide ligands in the same T cell receptor/major histocompatibility complex system.Statistical evaluations yielded significant differences in the initial relaxation process between sets of peptides at four different immunogenicity levels.

View Article: PubMed Central - PubMed

Affiliation: Center for Medical Statistics, Informatics and Intelligent Systems, Section for Biosimulation and Bioinformatics, Medical University of Vienna, Vienna, Austria. bernhard.knapp@meduniwien.ac.at

ABSTRACT
The interaction between the T cell receptor and the major histocompatibility complex is one of the most important events in adaptive immunology. Although several different models for the activation process of the T cell via the T cell receptor have been proposed, it could not be shown that a structural mechanism, which discriminates between peptides of different immunogenicity levels, exists within the T cell receptor. In this study, we performed systematic molecular dynamics simulations of 172 closely related altered peptide ligands in the same T cell receptor/major histocompatibility complex system. Statistical evaluations yielded significant differences in the initial relaxation process between sets of peptides at four different immunogenicity levels.

Show MeSH