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Open AccessArticle

APE-Gen: A Fast Method for Generating Ensembles of Bound Peptide-MHC Conformations

Department of Computer Science, Rice University, Houston, TX 77005, USA
Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA
Department of Chemistry, Rice University, Houston, TX 77005, USA
Author to whom correspondence should be addressed.
Academic Editors: Filip Jagodzinski and Brian Y. Chen
Molecules 2019, 24(5), 881;
Received: 15 January 2019 / Revised: 26 February 2019 / Accepted: 27 February 2019 / Published: 2 March 2019
The Class I Major Histocompatibility Complex (MHC) is a central protein in immunology as it binds to intracellular peptides and displays them at the cell surface for recognition by T-cells. The structural analysis of bound peptide-MHC complexes (pMHCs) holds the promise of interpretable and general binding prediction (i.e., testing whether a given peptide binds to a given MHC). However, structural analysis is limited in part by the difficulty in modelling pMHCs given the size and flexibility of the peptides that can be presented by MHCs. This article describes APE-Gen (Anchored Peptide-MHC Ensemble Generator), a fast method for generating ensembles of bound pMHC conformations. APE-Gen generates an ensemble of bound conformations by iterated rounds of (i) anchoring the ends of a given peptide near known pockets in the binding site of the MHC, (ii) sampling peptide backbone conformations with loop modelling, and then (iii) performing energy minimization to fix steric clashes, accumulating conformations at each round. APE-Gen takes only minutes on a standard desktop to generate tens of bound conformations, and we show the ability of APE-Gen to sample conformations found in X-ray crystallography even when only sequence information is used as input. APE-Gen has the potential to be useful for its scalability (i.e., modelling thousands of pMHCs or even non-canonical longer peptides) and for its use as a flexible search tool. We demonstrate an example for studying cross-reactivity. View Full-Text
Keywords: MHC class I; ensemble; molecular docking; peptide binding MHC class I; ensemble; molecular docking; peptide binding
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Abella, J.R.; Antunes, D.A.; Clementi, C.; Kavraki, L.E. APE-Gen: A Fast Method for Generating Ensembles of Bound Peptide-MHC Conformations. Molecules 2019, 24, 881.

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