Ape sequence analysis3/12/2023 ![]() The determinants that specifically interact with these antibodies have been designated as the antibody epitopes. Antibody recognition of donor HLA is dependent on the patient’s immune reactivity towards determinants on these mismatched donor HLA. The formation and/or presence of antibodies towards the mismatched donor HLA plays an important role in that. Histocompatibility of patients and organ donors has been shown to correlate with long-term graft survival in organ transplantation ( 1). To support studies on epitope analyses in organ transplantation, the calculation of donor-allele-specific solvent-accessible amino acid mismatches was implemented as a cloud-based web service. Our data suggest B-cell epitope definitions can be refined by considering allele-specific solvent-accessibility, rather than aggregating HLA protein surface maps by HLA class or locus. Mapping these data to antibody-verified epitopes as defined by the HLA Epitope Registry reveals patterns of (1) consistently accessible residues, (2) only subsets of an epitope’s residues being consistently accessible and (3) varying surface accessibility of residues of epitopes. Hence, residues may be surface-accessible on e.g. Although HLA Class I proteins predominantly are folded similarly, we found higher variation in root mean square difference of solvent accessibility between experimental structures of different HLAs compared to structures with identical amino acid sequence, suggesting HLA’s solvent accessible surface is protein specific. For each of the predicted structures, 10 known binding peptides as reported by the Immune Epitope DataBase were rendered into the binding groove. We extracted 676 HLA Class-I experimental structures from the Protein Data Bank and supplemented it by 37 Class-I alleles for which structures were predicted. This dataset trained a four-layer long short-term memory bidirectional recurrent neural network, which in turn inferred solvent accessibility of all known HLA Class I proteins. We developed a computational pipeline named Snowflake to calculate solvent accessibility of HLA Class I proteins for deposited HLA crystal structures, supplemented by constructed HLA structures through the AlphaFold protein folding predictor and peptide binding predictions of the APE-Gen docking framework. We hypothesized that HLA solvent accessibility is allele-specific, thus supporting refinement of HLA B-cell epitope prediction. Although recent advances in matching of both B-cell epitopes and T-cell epitopes have improved understanding of allorecognition, the immunogenic determinants are still not fully understood. Histocompatibility in solid-organ transplantation has a strong impact on long-term graft survival. ![]() 3Central Diagnostic Laboratory, University Medical Center, Utrecht, Netherlands.2Center for Translational Immunology, University Medical Center, Utrecht, Netherlands.1Research and Development, PIRCHE AG, Berlin, Germany.
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