The Dynamics of the Human Leukocyte Antigen Head Domain Modulates Its Recognition by the T-Cell Receptor
|Author||García Guerrero, Estefanía
Pérez Simón, José Antonio
Sánchez Abarca, Luis Ignacio
Díaz Moreno, Irene
Rosa Acosta, Miguel Ángel de la
Díaz Quintana, Antonio Jesús
|Department||Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular|
|Published in||PLoS One, 11 (4), e0154219.1-e0154219.18.|
|Abstract||Generating the immune response requires the discrimination of peptides presented by the
human leukocyte antigen complex (HLA) through the T-cell receptor (TCR). However, how
a single amino acid substitution in the antigen ...
Generating the immune response requires the discrimination of peptides presented by the human leukocyte antigen complex (HLA) through the T-cell receptor (TCR). However, how a single amino acid substitution in the antigen bonded to HLA affects the response of T cells remains uncertain. Hence, we used molecular dynamics computations to analyze the molecular interactions between peptides, HLA and TCR. We compared immunologically reactive complexes with non-reactive and weakly reactive complexes. MD trajectories were produced to simulate the behavior of isolated components of the various p-HLA-TCR complexes. Analysis of the fluctuations showed that p-HLA binding barely restrains TCR motions, and mainly affects the CDR3 loops. Conversely, inactive p-HLA complexes displayed significant drop in their dynamics when compared with its free versus ternary forms (p-HLA-TCR). In agreement, the free non-reactive p-HLA complexes showed a lower amount of salt bridges than the responsive ones. This resulted in differences between the electrostatic potentials of reactive and inactive p-HLA species and larger vibrational entropies in non-elicitor complexes. Analysis of the ternary p-HLA-TCR complexes also revealed a larger number of salt bridges in the responsive complexes. To summarize, our computations indicate that the affinity of each p-HLA complex towards TCR is intimately linked to both, the dynamics of its free species and its ability to form specific intermolecular salt-bridges in the ternary complexes. Of outstanding interest is the emerging concept of antigen reactivity involving its interplay with the HLA head sidechain dynamics by rearranging its salt-bridges.
|Cite||García Guerrero, E., Pérez Simón, J.A., Sánchez Abarca, L.I., Díaz Moreno, I., Rosa Acosta, M.Á.d.l. y Díaz Quintana, A. (2016). The Dynamics of the Human Leukocyte Antigen Head Domain Modulates Its Recognition by the T-Cell Receptor. PLoS One, 11 (4), e0154219.1-e0154219.18.|