DOI: 10.5061/dryad.gmsbcc2hx
title: Sequence-structure-function relationships in class I MHC: a local frustration perspective

description: Class I Major Histocompatibility Complex (MHC) binds short antigenic
 peptides with the help of Peptide Loading Complex (PLC), and presents them
 to T-cell Receptors (TCRs) of cytotoxic T-cells and Killer-cell
 Immunglobulin-like Receptors (KIRs) of Natural Killer (NK) cells. With
 more than 10000 alleles, the Human Leukocyte Antigen (HLA) chain of MHC is
 the most polymorphic protein in humans. This allelic diversity provides a
 wide coverage of peptide sequence space, yet does not affect the
 three-dimensional structure of the complex. Moreover, TCRs mostly interact
 with pMHC in a common diagonal binding mode, and KIR-pMHC interaction is
 allele-dependent. With the aim of establishing a framework for
 understanding the relationships between polymorphism (sequence), structure
 (conserved fold) and function (protein interactions) of the MHC, we
 performed here a local frustration analysis on pMHC homology models
 covering 1436 HLA I alleles. An analysis of local frustration profiles
 indicated that (1) variations in MHC fold are unlikely due to
 minimally-frustrated and relatively conserved residues within the HLA
 peptide-binding groove, (2) high frustration patches on HLA helices are
 either involved in or near interaction sites of MHC with the TCR, KIR, or
 Tapasin of the PLC, and (3) peptide ligands mainly stabilize the F-pocket
 of HLA binding groove.
description: Data collection
 for <strong>records_matureHLA.fasta</strong>: The sequences
 contained in this fasta file were obtained from the IMGT/HLA dataset. Only
 HLA binding groove residues are included (residues 1-180).
 Data collection
 for <strong>data_frame_SRFI.csv: </strong>This table includes
 mainly single residue frustration index data from pMHC structures covering
 1436 HLA Class I alleles in complex with 3-10 nonamer peptides. 3-10 high
 affinity peptide ligands were predicted using netMHCpan 3.0 for each
 allele, then homology models were created using Modeller v9.19. Local
 frustration analysis was then carried out using frustratometer2
 (stand-alone version from https://github.com/gonzaparra/frustratometer2 was used). The column names are as obtained from frustratometer2. <strong>FrstIndex </strong>column includes singe residue frustration index values. <strong>SASA,RSASA,Peptide,Allele </strong>columns include position-specific Solvent Accessible Surface Area (SASA), Relative SASA, peptide sequences and allele names, respectively. Data collection for <strong>df_SF_R_20200428.csv: </strong>This table includes a "reduced" version of <strong>data_frame_SRFI.csv, </strong>with following columns: Allele: specific HLA I allele name, Sequence: binding-groove sequence Chain: the chain on which the respective position is located Res: position of residue within the sequence AA: one-letter amino-acid code ChainRes: a concatenated string including Chain and Res fields. SASA, RSASA: as described above FI_mean, FI_mean_sd, FI_median: Mean and median SRFI values calculated for each position using data_frame_SRFI. FI_mean_sd denotes standart-deviation of mean SRFI values. rvET: Position-specific real-value Evolutionary Trace scores. FI_median_diff: The difference in median SRFI values upon peptide-binding. Locus: Gene Locus (A, B or C) Core Allele: True, if the allele is among the core alleles reported by Robinson et al. (2017) (https://doi.org/10.1371/journal.pgen.1006862). False, otherwise. Pocket: The peptide-binding pocket in which the respective residue is located. None if the residue is not included in any pocket. Interface: True, if the residue is a protein-protein interface residue within the MHC SS: Secondary-structure assignment Domain: The structural domain in which the respective residue in located.
description: For most alleles, 10 peptide ligands are included. For some
 alleles, however, netMHCpan 3.0 did not classify at least 10 peptides
 among 25000 random nonamer sequences as strong binders. Therefore, only
 those peptides classified as strong binders for these alleles were used in
 homology models, which resulted in less than 10 peptide ligands for some
 alleles. It should be sufficient to reproduce
 SRFI-based figures using only data included
 in <strong>df_SF_R_20200428.csv</strong>. Note that some of
 the data, such as solvent-accessible surface areas and secondary structure
 assignments were not used in the final publication.