Bio Interaction Databases

Version Compatibility

Reference examples tested with: requests 2.31+, pandas 2.2+, networkx 3.2+; STRING v12.0, BioGRID 4.4+, IntAct (live), SIGNOR 3.0+, OmniPath (live)

Before using code patterns, verify installed versions match. If versions differ:

• Python: pip show requests pandas networkx
• API surface: confirm endpoint URLs match each resource's current docs

STRING URL is version-pinned (version-12-0 as of 2024); older URLs (version-11-5) were deprecated 2023. The Cytoscape/Cytoscape.js ecosystem uses different version semantics; check the docs for the targeted version.

Interaction Databases

"Get protein-protein interactions for these genes" -> The choice of database matters more than the choice of API. Different resources index different evidence (physical binding, functional association, genetic interaction, signed signaling), with different curation pipelines (manually curated vs high-throughput vs text-mined), different species coverage, and different licenses.

The decision matrix below is the postdoc-grade view: what question is being asked, and which resource answers it best?

• Python: requests.get() against REST endpoints; pandas for parsing; networkx for graphs
• R: STRINGdb, OmnipathR (mature Bioconductor clients)
• Web: STRING, BioGRID, IntAct, SIGNOR, OmniPath, ConsensusPathDB browsers

Required Setup

import requests
import pandas as pd
import networkx as nx
from io import StringIO

CALLER = 'bioskills-2026'  # STRING + OmniPath accept caller_identity for usage attribution

API key requirements:

• BioGRID: free key required (https://webservice.thebiogrid.org/)
• STRING, IntAct, SIGNOR, OmniPath, Reactome: no key

Decision matrix: which resource for which question?

OmniPath (Türei et al. 2021 Mol Sys Biol 17:e9923) deserves special mention: it aggregates >100 sources into a unified API with provenance tracking. For "give me all available interactions for X" workflows, OmniPath is the modern default.

STRING (v12, channels, confidence)

STRING (Szklarczyk et al. 2023 Nucleic Acids Res 51:D638) aggregates evidence into a combined confidence score. The seven evidence channels:

The default score is the combined-evidence score (0-1000). Confidence tiers:

Version pinning: STRING URL is https://version-12-0.string-db.org/api/... as of 2024. Older version-11-5 URLs were deprecated 2023 — code using them silently fails. Use the unversioned https://string-db.org/api/... to follow the current release, or pin to a specific version for reproducibility.

caller_identity: STRING requests all programmatic users pass caller_identity=<app-name> for usage attribution. The parameter helps STRING identify and contact heavy automated callers.

BioGRID (physical + genetic, curated + HT)

BioGRID (Oughtred et al. 2021 Protein Sci 30:187) covers physical and genetic interactions across the broadest organism set of any major resource. Requires a free API key (https://webservice.thebiogrid.org/).

Key concepts:

• EXPERIMENTAL_SYSTEM: e.g. "Two-hybrid", "Affinity Capture-MS", "Synthetic Growth Defect"
• THROUGHPUT: "Low Throughput" vs "High Throughput" — the most important quality flag
• EVIDENCE_TYPE: physical vs genetic

For high-confidence physical interactions, filter to physical systems + Low Throughput:

PHYSICAL_LT_SYSTEMS = {
    'Affinity Capture-MS', 'Affinity Capture-Western', 'Affinity Capture-RNA',
    'Co-fractionation', 'Co-purification', 'Reconstituted Complex',
    'Co-crystal Structure', 'Two-hybrid', 'Far Western', 'FRET', 'PCA',
}

IntAct (PSI-MI curated physical)

IntAct (Del Toro et al. 2022 Nucleic Acids Res 50:D648) is the IMEx consortium reference for curated physical interactions in PSI-MI standard format. MINT was folded in ~2014; queries to MINT URLs now redirect to IntAct.

Direct REST API has changed multiple times; the most stable access is via OmniPath (which wraps IntAct) or via the PSICQUIC web services.

SIGNOR (signed signaling)

SIGNOR (Lo Surdo et al. 2023 Nucleic Acids Res 51:D631) is the only major curated database with signed, directed, mechanism-typed interactions. Each edge has:

• direction: A->B
• effect: up-regulates, down-regulates, unknown
• mechanism: phosphorylation, dephosphorylation, ubiquitination, binding, etc.

Essential for any signaling pathway analysis or dynamic modeling. Coverage smaller than STRING/BioGRID but quality is high.

Reactome (curated pathways)

Reactome (Milacic et al. 2024 Nucleic Acids Res 52:D672) is gold-standard for human pathway curation with full interaction reactions. Species-specific (human is by far the most complete).

Reactome ContentService REST: https://reactome.org/ContentService/.

HuRI / HuMAP (human-specific interactomes)

• HuRI (Luck et al. 2020 Nature 580:402): yeast-2-hybrid interactome of human; ~53K binary interactions; biased toward binary high-confidence.
• HuMAP v2 (Drew et al. 2021 Mol Syst Biol 17:e10016): AP-MS-derived complex map; integrates >15,000 proteomic experiments.

Both available for download; HuRI also has a web portal (http://www.interactome-atlas.org/).

OmniPath (meta-database)

OmniPath (Türei et al. 2021 Mol Syst Biol 17:e9923) aggregates 100+ sources with provenance. Key endpoints:

Each interaction includes sources (list of contributing databases) and references (PMIDs). For "give me everything anyone has said about A-B", OmniPath is the answer.

R users: OmnipathR (Bioconductor) is more ergonomic than raw HTTP.

License gotchas (critical for commercial use)

For commercial pipelines, stick to STRING + BioGRID + IntAct + SIGNOR + Reactome + HuRI/HuMAP + OmniPath with appropriate source attribution. Avoid ConsensusPathDB and PhosphoSitePlus without legal review.

Code patterns

STRING network with confidence threshold and channel inspection

Goal: Build a network of interactions among a gene list at a stated confidence; surface which channels contribute.

Approach: REST /network endpoint; parse channel-specific scores from response columns.

Reference (STRING v12.0):

import requests
import pandas as pd
from io import StringIO

STRING = 'https://version-12-0.string-db.org/api'


def get_string_network(genes, species=9606, threshold=700):
    '''threshold: 150 (low), 400 (medium), 700 (high), 900 (highest).'''
    url = f'{STRING}/tsv/network'
    params = {
        'identifiers': '%0d'.join(genes),
        'species': species,
        'required_score': threshold,
        'caller_identity': 'bioskills-2026',
    }
    r = requests.get(url, params=params); r.raise_for_status()
    df = pd.read_csv(StringIO(r.text), sep='\t')
    # Columns: stringId_A, stringId_B, preferredName_A, preferredName_B, ncbiTaxonId,
    # score, nscore (neighborhood), fscore (fusion), pscore (cooccurrence),
    # ascore (coexpression), escore (experiments), dscore (database), tscore (textmining)
    return df


genes = ['TP53', 'BRCA1', 'MDM2', 'ATM', 'CHEK2', 'CDK2']
df = get_string_network(genes, threshold=700)
print(f'{len(df)} interactions at score >= 700')
print('Channel composition for first 5 edges:')
print(df[['preferredName_A', 'preferredName_B', 'score',
          'escore', 'dscore', 'tscore', 'ascore']].head())

BioGRID physical interactions, low-throughput only

Reference (BioGRID 4.4+):

BIOGRID = 'https://webservice.thebiogrid.org/interactions/'

# Use the PHYSICAL_LT_SYSTEMS set defined above (the full curated set).
# Importing or re-defining is equivalent; using the same constant keeps the filter consistent.


def biogrid_lt_physical(gene, api_key, taxon=9606):
    params = {
        'accesskey': api_key,
        'format': 'json',
        'searchNames': True,
        'geneList': gene,
        'taxId': taxon,
        'includeInteractors': True,
        'max': 10000,
    }
    r = requests.get(BIOGRID, params=params); r.raise_for_status()
    data = r.json()
    rows = []
    for v in data.values():
        if v['THROUGHPUT'] == 'Low Throughput' and v['EXPERIMENTAL_SYSTEM'] in PHYSICAL_LT_SYSTEMS:
            rows.append({
                'gene_a': v['OFFICIAL_SYMBOL_A'],
                'gene_b': v['OFFICIAL_SYMBOL_B'],
                'system': v['EXPERIMENTAL_SYSTEM'],
                'pmid': v['PUBMED_ID'],
            })
    return pd.DataFrame(rows)

SIGNOR signed signaling

SIGNOR = 'https://signor.uniroma2.it/getData.php'


def signor_for_gene(gene_symbol):
    '''Return signed, directed signaling interactions involving the gene.'''
    params = {'organism': 'human', 'entity': gene_symbol}
    r = requests.get(SIGNOR, params=params); r.raise_for_status()
    rows = []
    for line in r.text.strip().split('\n')[1:]:
        cols = line.split('\t')
        if len(cols) >= 8:
            rows.append({
                'source': cols[0], 'target': cols[1], 'effect': cols[2],
                'mechanism': cols[3], 'pmid': cols[7],
            })
    return pd.DataFrame(rows)

OmniPath interactions (meta-database)

OMNI = 'https://omnipathdb.org'


def omnipath_interactions(genes, types='post_translational'):
    '''types: post_translational, transcriptional, mirna_target, lncrna_target.'''
    params = {
        'genesymbols': 1,
        'fields': 'sources,references,curation_effort,n_resources',
        'partners': ','.join(genes),
        'types': types,
        'license': 'academic',  # or 'commercial' for permissive-only sources
    }
    r = requests.get(f'{OMNI}/interactions', params=params); r.raise_for_status()
    df = pd.read_csv(StringIO(r.text), sep='\t')
    return df


df = omnipath_interactions(['TP53', 'MDM2', 'BRCA1'])
# Rich metadata: directionality, sign, sources, references, curation effort
print(df[['source_genesymbol', 'target_genesymbol', 'is_directed', 'is_stimulation',
          'is_inhibition', 'n_resources', 'n_references']].head())