Differential structural dynamics and antigenicity of two similar influenza H5N1 virus HA-specific HLA-A*0201-restricted CLT epitopes

Abstract

The presentation of viral peptides by major histocompatibility complex (MHC) molecules for T cell receptor (TCR) recognition is the central event in the development of T cell immunity against viruses. Molecular dynamics (MD) simulation is a powerful tool that is able to provide dynamic information, rather than a static view, of the mechanisms of peptide presentation in the antigen binding grooves of MHCs. In this paper, MD simulations are presented for two influenza H5N1 virus HA-specific cytotoxic T lymphocyte (CTL) epitopes, RI-10 (RLYQNPTTYI) and KI-10 (KLYQNPTTYI), in complex with HLA-A*0201. Although the amino acid sequence difference between RI-10 and KI-10 is slight, the structural dynamics of the two peptides were found to differ substantially. Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) calculations, and the thermal stability of the two complexes determined from their circular dichroism (CD) spectra, suggested that RI-10 had a higher binding free energy to HLA-A*0201 than KI-10. Furthermore, the structural fluctuation of the RI-10–HLA-A*0201 complex was found to be significantly lower than that of KI-10–HLA-A*0201. The distinctive salt bridges formed between Arg1 of RI-10 with Glu63 of HLA-A*0201 and the stronger hydrogen bond network may contribute to different structural dynamics between the two pMHC complexes through dynamic allosteric interaction mechanisms. RI-10-containing H5N1 virus strains isolated from Chinese patients are much less prevalent than KI-10-containing strains; this correlates with the higher antigenic potency of RI-10 in comparison to KI-10, as demonstrated in HLA-A*0201/K^b transgenic mice immunized with the two peptides.