Molecular dynamics and structure-based drug design for predicting non-natural nonapeptide binding to a class I MHC protein

Starting from the known three-dimensional structure of the class I major histocompatibility complex-encoded HLA-B*2705 protein, three non-natural nonapeptides were designed to fit optimally the HLA-B*2705-binding groove. The optimization was performed using structure-based drug design methods and the fact that all the possible interactions of the secondary anchor residue (position 3) with its human leukocyte antigen-binding pocket (pocket D) in nature are not entirely utilized. 150 ps molecular-dynamics (MD) simulation in water was employed to study the stability of the bimolecular complexes with three non-natural peptides (P3 = homophenylalanine, β-naphthylalanine, α-naphthylalanine) as well as with the two natural homologues (P3 = Gly, Leu). Various structural and dynamical properties (atomic fluctuations, solvent-accessible surface areas, peptide Cα-atom positions) of the simulated bimolecular complexes were used to compare the three non-natural with the two natural ligands. Since the various molecular properties have been shown previously to be related to the binding affinity of nonapeptide ligands to the major histocompatibility complex (MHC) HLA-B*2705 protein, the MD data predict a rather higher stability of MHC–ligand complexes with the three non-natural peptides, suggesting that the unnatural peptides studied show an enhanced binding affinity to the HLA-B*2705 protein. These results are in agreement with the experimental values of a semi-quantitative in vitro assembly assay, performed on the five nonapeptides (P3 = Gly, Leu, homophenylalanine, β-naphthylalanine, α-naphthylalanine), which shows their ability to stabilize the native conformation of the HLA-B*2705 heavy chain and also shows that the three non-natural ligands bind with higher affinity (0.5 µM) to the MHC protein than the two natural homologues (40 µM). Thus, this study demonstrates that structural information combined with rational design and molecular-dynamics simulations can illustrate and predict MHC binding and potential T-cell epitope properties as well as contribute to the design of new non-peptidic MHC inhibitors that may be useful for the selective immunotherapy of autoimmune diseases to which HLA alleles are directly associated.