title: Anchor profiles of HLA-specific peptides: analysis by a novel affinity scoring method and experimental validation.
abstract: The study of intermolecular interactions is a fundamental research subject in biology. Here we report on the development of a quantitative structure-based affinity scoring method for peptide-protein complexes, named PepScope. The method operates on the basis of a highly specific force field function (CHARMM) that is applied to all-atom structural representations of peptide-receptor complexes. Peptide side-chain contributions to total affinity are scored after detailed rotameric sampling followed by controlled energy refinement. A de novo approach to estimate dehydration energies was developed, based on the simulation of individual amino acids in a solvent box filled with explicit water molecules. Transferability of the method was demonstrated by its application to the hydrophobic HLA-A2 and -A24 receptors, the polar HLA-A1, and the sterically ruled HLA-B7 receptor. A combined theoretical and experimental study on 39 anchor substitutions in FxSKQYMTx/HLA-A2 and -A24 complexes indicated a prediction accuracy of about two thirds of a log-unit in Kd. Analysis of free energy contributions identified a great role of desolvation and conformational strain effects in establishing a given specificity profile. Interestingly, the method rightly predicted that most anchor profiles are less specific than so far assumed. This suggests that many potential T-cell epitopes could be missed with current prediction methods. The results presented in this work may therefore significantly affect T-cell epitope discovery programs applied in the field of peptide vaccine development.
authors.affiliation: AlgoNomics NV, Gent-Zwijnaarde, Belgium. johan.desmet@algonomics.com <johan.desmet@algonomics.com>
authors.forename: Johan
authors.initials: J
authors.lastname: Desmet
authors.forename: Geert
authors.initials: G
authors.lastname: Meersseman
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boutonnet
authors.forename: Jurgen
authors.initials: J
authors.lastname: Pletinckx
authors.forename: Krista
authors.initials: K
authors.lastname: De Clercq
authors.forename: Maja
authors.initials: M
authors.lastname: Debulpaep
authors.forename: Tessa
authors.initials: T
authors.lastname: Braeckman
authors.forename: Ignace
authors.initials: I
authors.lastname: Lasters
mesh_terms: D000595:Amino Acid Sequence; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry*; D006680:HLA Antigens / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
chemical_list: D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D010455:Peptides