mhcseqs 2.2.0

MHC sequence curation and binding groove extraction

mhcseqs

Self-contained pipeline for downloading, curating, and extracting binding grooves from MHC (Major Histocompatibility Complex) protein sequences.

Install

pip install mhcseqs

For development:

git clone https://github.com/pirl-unc/mhcseqs.git
cd mhcseqs
./develop.sh          # uv pip install -e ".[dev]"
./test.sh             # pytest
./lint.sh             # ruff

Quick start

CLI

# Build all output CSVs (writes to ~/.cache/mhcseqs/)
mhcseqs build

# Build to a specific directory instead
mhcseqs build --output-dir output/

# Look up a specific allele
mhcseqs lookup "HLA-A*02:01"

# Check version
mhcseqs --version

Python API

import mhcseqs

# Build the database (downloads to ~/.cache/mhcseqs/, only needed once)
paths = mhcseqs.build()  # BuildPaths dataclass

# Look up any allele → AlleleRecord with everything
r = mhcseqs.lookup("HLA-A*02:01")
r.sequence          # full protein (with signal peptide)
r.mature_sequence   # signal peptide removed (computed property)
r.mature_start      # signal peptide length (24 for HLA-A*02:01)
r.groove1           # α1 domain
r.groove2           # α2 domain
r.ig_domain         # α3 Ig-fold
r.tail              # TM + cytoplasmic
r.domains           # typed domain spans
r.domain_architecture
r.domain_spans
r.species_category  # "human"

# Apply mutations (IEDB-style, e.g. "K66A")
m = mhcseqs.lookup("HLA-A*02:01", mutations=["K66A", "D77S"])

Load as a DataFrame

import mhcseqs

# As a DataFrame (full sequence + groove decomposition + metadata)
df = mhcseqs.load_sequences_dataframe()

# Or as a list of dicts (no pandas dependency)
rows = mhcseqs.load_sequences_dict()

Current data summary

Three sources are merged into a single dataset:

Source	Entries	Species	Notes
IMGT/HLA	44,630	Human	Downloaded at build time
IPD-MHC	12,380	Non-human mammals, birds, fish	Downloaded at build time
UniProt	20,566	500+ species	Curated diverse MHC, B2M, H-2 references (shipped in package)
Total raw	77,576
After merge/dedup	55,658		One representative per two-field allele
Groove OK	54,098		97.2% of representatives

By species category

Category	Count	Groove OK	Class I full	Class II full
human	25,364	99.8%	17,426	5,347
nhp	7,125	98.0%	4,583	1,426
bird	9,312	98.9%	546	562
fish	4,859	97.4%	776	1,259
ungulate	1,768	94.7%	577	303
murine	1,587	89.7%	490	118
carnivore	484	99.6%	164	0
other_mammal	943	95.1%	280	146
other_vertebrate	1,137	96.0%	324	129

"Groove OK" includes both full-length and fragment parses. "Full" means both groove halves present (class I: α1 + α2, ~183 aa; class II: single chain's groove half with Ig support, ~88 aa groove + ~90 aa Ig). The remaining entries are single-exon fragments (one groove half only) — common in bird and fish submissions to IPD-MHC where only the polymorphic exon is sequenced. The parser correctly characterizes these as alpha1_only, alpha2_only, beta1_only_fallback, or fragment_fallback.

Species categories: human, nhp (non-human primates), murine (mice, rats, rodents), ungulate (cattle, pig, horse, sheep, goat), carnivore (dog, cat), other_mammal (marsupials, monotremes, bats, cetaceans, rabbit), bird, fish, other_vertebrate (reptiles, amphibians).

Signal peptide detection accuracy

Validated against 2,403 UniProt ground-truth SP annotations:

Species	Class I exact	Class II exact
Human	99.2%	88.4%
NHP	100.0%	91.2%
Bird	94.4%	89.3%
Fish	86.9%	81.9%
Other vertebrate	68.2%	86.1%
Overall	82.0% exact, 89.9% within ±2 aa

False positive rate on 2,155 mature-only controls: 3.8%.

Data directory

By default, mhcseqs build downloads FASTA files and writes output CSVs to ~/.cache/mhcseqs/ (override with $MHCSEQS_DATA or --output-dir).

~/.cache/mhcseqs/
├── fasta/                     # Downloaded FASTA source files
│   ├── hla_prot.fasta         # IMGT/HLA (human)
│   └── ipd_mhc_prot.fasta    # IPD-MHC (non-human)
├── mhc-seqs-raw.csv           # Every protein entry from all sources
├── mhc-full-seqs.csv          # One representative per two-field allele (with grooves)
├── mhc-merge-report.txt       # Deduplication decisions
└── mhc-validation-report.txt  # Sanity checks

Structural decomposition

The parser materializes an explicit domain grammar:

Chain	Grammar
Class I alpha	signal_peptide? -> g_alpha1 -> g_alpha2 -> c1_alpha3 -> transmembrane? -> cytoplasmic_tail?
Class II alpha	signal_peptide? -> g_alpha1 -> c1_alpha2 -> transmembrane? -> cytoplasmic_tail?
Class II beta	signal_peptide? -> g_beta1 -> c1_beta2 -> transmembrane? -> cytoplasmic_tail?

The exported contiguous sequence fields are:

Column	Class I alpha	Class II alpha	Class II beta
groove1	α1 domain (~80-95 aa typical)	α1 domain (~75-95 aa typical)	—
groove2	α2 domain (~80-100 aa typical)	—	β1 domain (~70-100 aa typical)
ig_domain	α3 C-like support domain	α2 C-like support domain	β2 C-like support domain
tail	linker + TM + cytoplasmic tail	linker + TM + cytoplasmic tail	linker + TM + cytoplasmic tail

domain_architecture and domain_spans expose the typed domain grammar directly, for example:

• class I: signal_peptide>g_alpha1>g_alpha2>c1_alpha3>tail_linker>transmembrane>cytoplasmic_tail
• class II beta: signal_peptide>g_beta1>c1_beta2>tail_linker>transmembrane>cytoplasmic_tail

How Parsing Works

The parser is alignment-free and holistic. It does not rely on one absolute Cys position to define the mature start.

For each sequence it:

1. Enumerates all plausible Cys-Cys pairs in the Ig/C-like separation range.
2. Scores each pair as a candidate G-domain or C-like anchor using fold-topology evidence, especially the Trp41-like signal around c1+14.
3. Enumerates candidate SP boundaries and whole domain parses, including partial parses when only fragment evidence is available.
4. Chooses the best full parse using factored multiplicative scoring: three structural claims (SP grammar, domain architecture, completeness) each produce a [0,1] factor. Contradictory evidence in any factor gates the score down multiplicatively, while missing evidence is a softer penalty.

The strongest evidence types are:

• SP cleavage grammar: hydrophobic h-region, short c-region, von Heijne -3/-1 compatibility, exclusion of impossible -3/-1 property pairs, and mild +1 mature-sequence penalties.
• Domain-fold grammar: canonical G-domain versus C-like disulfide topology, including the IMGT-style Cys11-Cys74 G-domain signature and the Cys23/Trp41/Cys104 C-like grammar.
• Class-specific groove boundaries:
  • class I α1/α2 junction motifs
  • class I α2 -> α3 boundary motifs
  • class II α1 -> α2 and β1 -> β2 boundary motifs
• Soft priors on groove/support-domain lengths and TM support downstream.

The parser handles:

• full-length proteins with or without signal peptides
• SP-stripped deposits (mature_start = 0)
• common fragments:
  • class I exon 2 only -> alpha1_only
  • class I exon 3 only -> alpha2_only
  • class II exon 2-like fragments -> fragment_fallback
• low-evidence salvage:
  • class I from α3 C-like support only -> inferred_from_alpha3
  • class II beta from β1 groove pair only -> beta1_only_fallback
• true groove absence / insufficient structural evidence -> missing_groove

Groove Status Values

These are the important parser-facing statuses:

Status	Meaning
ok	Full decomposition from the main structural grammar
alpha1_only	Class I fragment consistent with α1 / exon 2 only
alpha2_only	Class I fragment consistent with α2 / exon 3 only
fragment_fallback	Short fragment retained as the observable groove half
inferred_from_alpha3	Class I salvage parse using a downstream α3 C-like anchor
beta1_only_fallback	Class II beta salvage parse using only the β1 groove pair
missing_groove	No recoverable groove architecture from the available evidence
non_classical	Non-classical class-I lineage flagged post-parse
short	Groove half too short to look functionally peptide-binding

Pipeline-only statuses can still appear in CSV outputs:

Status	Meaning
not_applicable	Row intentionally excluded from groove functionality, mainly B2M in build outputs

Literature Basis

The parser is built around conserved sequence grammar from the MHC literature:

• MHC domain organization is more conserved than short local motifs across vertebrates: Primordial Linkage of β2-Microglobulin to the MHC
• IMGT domain numbering and the G-domain versus C-like disulfide grammar: PMC3913909
• Classical class-I domain layout and landmarks: PMC2434379
• Salmonid class-II alpha/beta cysteine topology and lineage-specific extra cysteines: PMC2386828
• Teleost class-II evolutionary divergence while retaining the same modular architecture: PMC4219347

Signal-peptide logic follows the standard SPase grammar:

• von Heijne -3/-1 cleavage rule: How signal sequences maintain cleavage specificity
• flanking -2/+1 effects: Flanking signal and mature peptide residues influence signal peptide cleavage
• strong penalty for +1 Pro: PubMed 1544500
• h-region / c-region structural context: Structure of the human signal peptidase complex reveals the determinants for signal peptide cleavage

Key columns

Column	Description
two_field_allele	Allele name at two-field resolution
gene	MHC gene (e.g., A, DRB1, BF, UA)
mhc_class	I or II
chain	alpha, beta, or B2M
species	Latin binomial from source
species_category	One of 9 categories above
source	imgt, ipd_mhc, or uniprot
source_id	Database accession for provenance
groove_status	See table above
is_functional	True if groove parsed and not null/pseudogene

Dependencies

• Python 3.10+
• mhcgnomes >= 3.14.0 — allele name parsing with species-directed disambiguation

No alignment tools, BLAST, or structure databases are required.

License

Apache 2.0