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Title: The Dynamics of the Human Leukocyte Antigen Head Domain Modulates Its Recognition by the T-Cell Receptor.
Authors: García-Guerrero, Estefanía
Pérez-Simón, José Antonio
Sánchez-Abarca, Luis Ignacio
Díaz-Moreno, Irene
De la Rosa, Miguel A
Díaz-Quintana, Antonio
metadata.dc.subject.mesh: Amino Acid Sequence
Antigen Presentation
Binding Sites
HLA Antigens
Molecular Dynamics Simulation
Protein Binding
Protein Interaction Domains and Motifs
Protein Structure, Secondary
Receptors, Antigen, T-Cell
Static Electricity
Issue Date: 28-Apr-2016
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 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.
metadata.dc.identifier.doi: 10.1371/journal.pone.0154219
Appears in Collections:Producción 2020

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