Scrutinizing MHC-I Binding Peptides and Their Limits of Variation

Christian P Koch, Anna M Perna, Max Pillong, Nickolay K Todoroff, Paul Wrede, Gerd Folkers, Jan A Hiss and Gisbert Schneider

PLOS Computational Biology, 2013, vol. 9, issue 6, 1-9

Abstract: Designed peptides that bind to major histocompatibility protein I (MHC-I) allomorphs bear the promise of representing epitopes that stimulate a desired immune response. A rigorous bioinformatical exploration of sequence patterns hidden in peptides that bind to the mouse MHC-I allomorph H-2Kb is presented. We exemplify and validate these motif findings by systematically dissecting the epitope SIINFEKL and analyzing the resulting fragments for their binding potential to H-2Kb in a thermal denaturation assay. The results demonstrate that only fragments exclusively retaining the carboxy- or amino-terminus of the reference peptide exhibit significant binding potential, with the N-terminal pentapeptide SIINF as shortest ligand. This study demonstrates that sophisticated machine-learning algorithms excel at extracting fine-grained patterns from peptide sequence data and predicting MHC-I binding peptides, thereby considerably extending existing linear prediction models and providing a fresh view on the computer-based molecular design of future synthetic vaccines. The server for prediction is available at http://modlab-cadd.ethz.ch (SLiDER tool, MHC-I version 2012).Author Summary: Future success in vaccine development will critically depend on identifying potent epitopes with reduced side effects. Among such candidate molecules, immunogenic peptides binding to major histocompatibility protein I (MHC-I) represent a preferred class of biomolecules for vaccine design. Computational models assist in the selection of the best candidate peptides by providing a mathematical rationale for antigen recognition by MHC-I. Here we present a machine-learning model that was trained on recognizing features of known MHC-I binding and non-binding peptide sequences with sustained accuracy. We were able to biochemically validate the computational predictions in a direct binding assay measuring complex formation between synthesized candidate peptides and MHC-I. Strong correspondence between the predictions and the experimentally determined binding potential corroborate the machine-learning model as viable for future antigen design. Thus, our study provides a concept for rapidly finding innovative MHC-I binding peptides with limited experimental effort.

Date: 2013
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1003088

DOI: 10.1371/journal.pcbi.1003088

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