Predicting HLA Class I Non-Permissive Amino Acid Residues Substitutions |
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Authors: | T Andrew Binkowski Susana R Marino Andrzej Joachimiak |
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Affiliation: | Biosciences Division, Argonne National Laboratory, Midwest Center for Structural Genomics, Argonne, Illinois, United States of America. |
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Abstract: | Prediction of peptide binding to human leukocyte antigen (HLA) molecules is essential to a wide range of clinical entities from vaccine design to stem cell transplant compatibility. Here we present a new structure-based methodology that applies robust computational tools to model peptide-HLA (p-HLA) binding interactions. The method leverages the structural conservation observed in p-HLA complexes to significantly reduce the search space and calculate the system's binding free energy. This approach is benchmarked against existing p-HLA complexes and the prediction performance is measured against a library of experimentally validated peptides. The effect on binding activity across a large set of high-affinity peptides is used to investigate amino acid mismatches reported as high-risk factors in hematopoietic stem cell transplantation. |
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