Journalclub: Molecular Dynamics simulations of TCRpMHC


T cells recognize fragments of pathogen (peptides) presented by the Major Histocompatibility Complex (MHC) via their T-cell receptor (TCR). This interaction process is commonly considered as one of the most important events taken place in the adaptive immune reaction.


Molecular Dynamics simulations are a computational technique to simulate the movement of atoms over time. For this purpose the interaction energies (bond and non-bond) between the single atoms are calculated and the spatial position are adjusted during each iteration. Such simulations are very resource and time consuming but provide insights into interaction processes which can not be obtained by any currently available experimental technique.

In this journal club we discussed 3 different papers dealing with MD simulations of the TCRpMHC complex:

A typical story

Epitope Flexibility and Dynamic Footprint Revealed by Molecular Dynamics of a pMHC-TCR Complex
Reboul et al., Plos Comp. Biol. 2012

Like similarly done by many other authors before Reboul et al. performed MD simulations of two different (however very similar MHCs) in complex with the same viral peptide. While no immune reaction is caused if the peptide is presented by HLA-B*3501 there is an reaction induced if presented in the context of HLA-B*3508.

In their MD simulations the authors find minor differences in the RMSF and claim this to be systematic and the cause for the different behaviour.

An innovative story

Toward an atomistic understanding of the immune synapse: Large-scale molecular dynamics simulation of a membrane embedded TCR–pMHC–CD4 complex
Wan et al., Molecular Immunology 2008

While several PDB structures of parts of the core of the immunological synapse are available (see image below). On overall structure was not published before this paper. This is addressed by the authors by means of superimposition, modelling of linking and trans-membrane regions, and subsequent MD simulation. The resulting structure seems to be in good agreement with experimental electron microscopy data.


My story

Early relaxation dynamics in the LC 13 T cell receptor in reaction to 172 altered peptide ligands: A molecular dynamics simulation study
Knapp et al., Plos One 2013

In most studies authors compare the same MHC but with two or three different peptides or the same peptide bound to 2 MHCs. In some cases also the same peptide and MHC are simulated in interaction with 2 different TCRs. Given the fact that the TCRpMHC consists of roughly 800 AAs one will almost certainly find some differences between those two or three simulations (multiple testing). Differences would also be present if one simulates the same complex twice with different starting velocities or more extreme even if one parametrizes the same velocities but different hardware is used. Yes, also in this case this may lead to slightly different results. On this basis such studies (if published without further experimental data to undermine the findings) are at best anecdotal stories.

Therefore we indented to address this challenge in a more systematic way: We simulated the LC 13 TCR / HLA-B*08:01 system in complex with all possible single point mutations in the EBV peptide FLRGRAYGL. This leads to a total of 172 highly related MD simulations where for each of them the experimental immunogenicity is known. Based on their immunogencity we assigned each simulations to either the more immunogenic (moreI) or less immunogenic (lessI) group. This was repeated for several thresholds.  Further analysis on the basis of RMSD maps and permutation tests showed that moreI and lessI groups were significantly different in their initial relaxation dynamics from the (perturbed) x-ray structure.


They were not only significantly different but they also showed a quite interesting pattern in their most frequently different regions (highlighted in green):


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