| Autor: |
Desmet, Johan, Meersseman, Geert, Boutonnet, Nathalie, Pletinckx, Jurgen, De Clercq, Krista, Debulpaep, Maja, Braeckman, Tessa, Lasters, Ignace |
| Zdroj: |
Proteins; Jan2005, Vol. 58 Issue 1, p53-69, 17p |
| Abstrakt: |
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 F xSKQYMT x/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. Proteins 2005. © 2004 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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