The Dynamics of the Human Leukocyte Antigen Head Domain Modulates Its Recognition by the T-Cell Receptor

• Published in: PloS one 2016-04, Vol.11 (4), p.e0154219-e0154219
• Main Authors: García-Guerrero, Estefanía, Pérez-Simón, José Antonio, Sánchez-Abarca, Luis Ignacio, Díaz-Moreno, Irene, De la Rosa, Miguel A, Díaz-Quintana, Antonio
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amino acid substitution; Amino acids; Analysis; Antigen Presentation; Antigens; Binding Sites; Biology and Life Sciences; Chemical bonds; Complementarity-determining region 3; Computer simulation; Cytochrome; Dynamic tests; Flexibility; Histocompatibility antigen HLA; HLA Antigens - chemistry; HLA Antigens - immunology; Humans; Immune complexes; Immune response; Immune system; Leukocytes; Lymphocytes; Lymphocytes T; Medicine and Health Sciences; Molecular dynamics; Molecular Dynamics Simulation; Molecular interactions; Mutation; Peptides; Peptides - chemistry; Peptides - immunology; Physical Sciences; Protein Binding; Protein Interaction Domains and Motifs; Protein Structure, Secondary; Receptors, Antigen, T-Cell - chemistry; Receptors, Antigen, T-Cell - immunology; Salts; Static Electricity; T cell antigen receptors; T cell receptors; T-cell receptor; Thermodynamics; Variation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0154219

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.