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

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.

The Next Vaccine Generation Against Malaria: Structurally Modulated Plasmodium Antigens

“…Thus, two peptido-mimetic analogues coded ψ-128 and ψ-130 which were modified between the 30 F-I 31 and 31 I-N 32 amino acid pairs, respectively, were obtained and characterized. Our experiments for a fine PfMSP2 [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] sequence mapping with monoclonal antibodies directed to both modified motifs have revealed a functional epitope whose exact location was 25 KYSNTFIN 32 as previously published [45].…”

“…Therefore, CD4 + T-lymphocyte proliferation would lead a subsequent neutralizing antibody production able to block the influenza virus infection, being this molecular interaction an effective mechanism effectively used for the immune response. As this a number of similar immuno-reactive complexes have been described [35][36][37][38][39][40].…”

“…In order to be consisting with our proposed molecular models, we decided to focus our attention in another relevant Plasmodium antigen, the so-named PfMSP-2 surface antigen. Specifically, we have designed and synthesized some reduced amide peptido-mimetics based on the N-terminus PfMSP2 [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] peptide whose amino acid sequence is KNESKYSNTFIN-NAYNMSIR. Thus, two peptido-mimetic analogues coded ψ-128 and ψ-130 which were modified between the 30 F-I 31 and 31 I-N 32 amino acid pairs, respectively, were obtained and characterized.…”

“…On the other hand, backbone structural analyses for the PfMSP2 [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] regarding its two ψ-128 ( 30 F-I 31 ) and ψ-130 ( 31 I-N 32 ) reduced amide peptido-mimetics, revealed a close-related behavior regarding the couple of the above discussed examples for a different Plasmodium protein, the PfMSP1. Figure 10C, displays the β-stranded conformation of the native sequence (solvent accessible surface depicted in white) regarding the more flexible conformations of both of its peptido-mimetics (represented by purple and ochre ribbons).…”

Selection of Tumor-Specific Cytotoxic T Lymphocytes in Acute Myeloid Leukemia Patients Through the Identification of T-Cells Capable to Establish Stable Interactions With the Leukemic Cells: “Doublet Technology”

“…In this sense, we have published that the pHLA-TCR interactions that involve immune reactive peptides are more stable and strong than those which do not induce a triggering of the TCR activation. In our model, the stabilization of the reactive complex was achieved due to less fluctuations and more salt bridges comparing with non-reactive peptides ( 31 ).…”