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

Abstract

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.

Keywords: MHC class I; ensemble; molecular docking; peptide binding.

Figure 1

Distribution of final full-atom RMSD across various peptide lengths. The average full-atom RMSD across whole dataset is 2.02 Å. There are a total of 93, 317, 91, and 34 structures of 8-mers, 9-mers, 10-mers, and 11-mers, respectively.

Figure 2

Modelling 15-mer peptide, FLNKDLEVDGHFVTM, onto HLA-A*02:01. The crystal structure is in blue (PDB code 4U6Y), while the modelled structure is in green. APE-Gen can generate a model of the peptide to 2.82 Å full-atom RMSD (1.57 Å C$\alpha$ RMSD)

Figure 3

View of T-cell interacting interface. (a) Ribbon view of MAGEA3 (pink) bound to HLA-A*01:01 (green), PDB code 5BRZ (b) Electrostatic surface of MAGEA3 bound to HLA-A*01:01, PDB code 5BRZ (c) Electrostatic surface of Titin-derived self-peptide bound to HLA-A*01:01 (APE-Gen model). APE-Gen can search for conformations Titin-derived self-peptide that produce similar pMHC interfaces to the reference MAGEA3 conformation. Electrostatic surfaces are computed using PyMOL’s “Protein Contact Potential” feature.

Figure 4

Steps within a single round of APE-Gen. From left to right: anchor alignment, peptide backbone sampling, and energy minimization. After a round is complete, the highest quality conformation as determined by the scoring function is used to initialize the next round.