3 research outputs found
The Dynamics of the Human Leukocyte Antigen Head Domain Modulates Its Recognition by the T-Cell Receptor
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-bridgesFinancial support was provided by the Spanish Ministry of Economy and Competiveness (Grant No. BFU2012-31670/BMC); The Andalusian Government (Grant PAI, BIO198); The Spanish Fund for Health Research (FIS; code PI11/02366, FI12/00189) and the RamĂłn Areces Foundation.Peer reviewe