---

name: tooluniverse-structural-proteomics description: Structural biology plus proteomics integration for drug target validation. Combines PDB experimental structures, AlphaFold predictions, GPCRdb, SAbDab antibody structures, ProteinsPlus binding-site prediction, BindingDB ligand-affinity data, BMRB NMR data, CATH/InterPro fold classification, intrinsic-disorder prediction (MobiDB/DisProt/IUPred3), membrane-protein topology (OPM/TopDB/PDBTM/ChannelsDB), enzyme catalytic-site data (M-CSA), PDBe ligand/compound chemistry, and MD simulation trajectory metadata (MDDB). Use for druggability assessment, binding-site characterization, ligand-pocket analysis, structural-confidence scoring (resolution, pLDDT), antibody-target interface analysis, disordered-region assessment, membrane-protein topology, catalytic-mechanism lookup, and finding published MD simulations for a target. disable-model-invocation: true

Structural Proteomics for Drug Target Validation

Comprehensive structural data integration using ToolUniverse tools across PDB, AlphaFold, GPCRdb, SAbDab, and proteomics databases for drug target validation.

LOOK UP DON'T GUESS

• PDB structures/resolutions: PDBeSIFTS_get_best_structures and RCSBGraphQL_get_structure_summary
• AlphaFold confidence: alphafold_get_summary
• Ligands/affinities: PDBe_get_structure_ligands and BindingDB_get_ligands_by_uniprot
• Protein-protein binding mutations (ddG): SKEMPI_search_by_structure/SKEMPI_search_by_protein/SKEMPI_get_mutation -- BindingDB's protein-protein equivalent, for interface-mutation affinity effects rather than small-molecule ligands
• Druggability: ProteinsPlus_predict_binding_sites

COMPUTE, DON'T DESCRIBE

When analysis requires computation (statistics, data processing, scoring, enrichment), write and run Python code via Bash. Don't describe what you would do — execute it and report actual results. Use ToolUniverse tools to retrieve data, then Python (pandas, scipy, statsmodels, matplotlib) to analyze it.

Domain Reasoning

Resolution determines valid conclusions: <2A = atom positions visible; 2-3A = side chains reliable, drug design supported; >3A = backbone only, binding site unreliable. Do not over-interpret low-resolution structures.

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Tool Inventory

PDB (RCSB)

RCSBAdvSearch_search_structures (query_type, query_value, rows), RCSBData_get_entry (entry_id), RCSBGraphQL_get_structure_summary (pdb_id), RCSBGraphQL_get_ligand_info (pdb_id), RCSB_get_chemical_component (comp_id)

PDB (PDBe)

pdbe_get_entry_summary (pdb_id), PDBe_get_structure_ligands (pdb_id), PDBe_get_bound_molecules (pdb_id), PDBeSearch_search_structures (query, rows), PDBeSIFTS_get_best_structures (uniprot_id), PDBeSIFTS_get_all_structures (uniprot_id), PDBe_KB_get_ligand_sites (pdb_id), PDBe_KB_get_interface_residues (pdb_id), PDBeValidation_get_quality_scores (pdb_id)

PDBe PISA

PDBePISA_get_interfaces (pdb_id), PDBePISA_get_assemblies (pdb_id)

AlphaFold

alphafold_get_prediction (qualifier=UniProt), alphafold_get_summary (qualifier), alphafold_get_annotations (qualifier)

Binding Sites

ProteinsPlus_predict_binding_sites (pdb_id, chain), BindingDB_get_ligands_by_uniprot (uniprot_id), BindingDB_get_ligands_by_pdb (pdb_id), BindingDB_get_targets_by_compound (smiles)

Ligand/Compound Chemistry (PDBe Compounds)

PDBe_get_compound_summary (comp_id — 3-letter PDB chemical-component code) — formula, weight, InChI/InChIKey, SMILES, systematic names, and cross-references to PubChem/DrugBank/EPA CompTox for one ligand. PDBe_get_compound_structures (comp_id) — see gotcha below, does not return an exhaustive structure list.

Foldseek

Foldseek_search_structure (sequence, mode="tmalign"), Foldseek_get_result (ticket)

GPCRdb

GPCRdb_get_protein (protein), GPCRdb_get_structures (protein), GPCRdb_get_ligands (protein), GPCRdb_get_mutations (protein). Accepts entry names, gene symbols (auto-converted to {symbol.lower()}_human), or UniProt accessions.

SAbDab

SAbDab_search_structures (query/antigen), SAbDab_get_structure (pdb_id), TheraSAbDab_search_therapeutics (query), TheraSAbDab_search_by_target (target)

Domains

InterPro_get_protein_domains (uniprot_id), Pfam_get_protein_annotations (uniprot_id), UniProt_get_entry_by_accession (accession)

Fold/Domain Classification (CATH + InterPro member databases)

CATH_get_superfamily (superfamily_id), CATH_get_domain_summary (domain_id), CATH_list_funfams (superfamily_id), CATH_get_funfam (superfamily_id, funfam_number), InterPro_list_member_databases (no params), InterPro_list_member_signatures (member_database, page_size), InterPro_get_member_signature (member_database, accession), InterPro_get_structures_for_entry (interpro_id, page_size)

Domain Architecture and Clans (InterPro, Pfam-accession-keyed)

InterPro_get_protein_domain_architecture (accession), InterPro_get_structures_for_domain (pfam_accession, max_results), InterPro_get_clan_members (clan_accession, max_results) — InterPro's API is intermittently flaky, see Workflow 5b below before assuming a "not found" result means the entry doesn't exist

Proteomics

ProteomeXchange_search_datasets (query), ProteomeXchange_get_dataset (dataset_id)

Molecular Dynamics Simulation Metadata (MDDB)

MDDB_search_projects (query, limit), MDDB_get_project (accession) — simulation parameters (force field, temperature, ensemble, simulated time, frames, trajectory size) for published MD trajectories; metadata only, not the trajectory files

BMRB (NMR data)

BMRB_search_by_keyword (term, database="macromolecules"|"metabolomics"), BMRB_search_by_sequence (sequence), BMRB_get_entries_by_pdb_id (pdb_id), BMRB_get_entries_by_uniprot (uniprot_id), BMRB_get_entry (entry_id), BMRB_get_entry_citation (entry_id), BMRB_get_validation (entry_id), BMRB_search_chemical_shifts (entry_id or search filters)

Intrinsic Disorder (MobiDB, DisProt, IUPred3)

MobiDB_get_protein (accession), MobiDB_get_consensus (accession) — currently unreachable, see Limitations. DisProt_search (query, page_size), DisProt_get_entry (accession — DisProt ID or UniProt accession). IUPred3_predict_disorder (accession, iupred_type="long"|"short"|"anchor")

Membrane Protein Structure (OPM, TopDB, PDBTM, ChannelsDB)

OPM_search_structures (query, limit), TopDB_get_topology (identifier), PDBTM_get_topology (pdb_id), ChannelsDB_get_channels_pdb (pdb_id), ChannelsDB_get_channels_cofactor (pdb_id)

Catalytic Site Atlas (M-CSA)

MCSA_get_entry (mcsa_id), MCSA_search_enzymes (enzyme_name, ec_number, uniprot_id, max_pages, limit)

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Workflow 1: Find All Structures for a Drug Target

Phase 0: Resolve protein → UniProt ID, gene symbol, organism
Phase 1: PDBeSIFTS_get_best_structures → RCSBGraphQL_get_structure_summary → PDBeValidation
Phase 2: alphafold_get_prediction/summary → compare pLDDT with experimental coverage
Phase 3: IF GPCR → GPCRdb; IF antibody target → SAbDab/TheraSAbDab
Phase 4: InterPro/Pfam domain mapping → identify unresolved regions
Phase 5: Summary table (PDB ID, method, resolution, ligands, coverage, quality)

Decisions: Resolution <2.5A for drug design. X-ray > Cryo-EM > NMR > AlphaFold for binding sites. Holo > apo structures. When a target's best experimental structure IS an NMR structure (common for small/disordered proteins where crystallography fails), or when dynamics/flexibility data matters more than a single static pocket geometry, pull the underlying chemical-shift/assignment data via BMRB (Workflow 4) rather than treating the PDB coordinate file as the only NMR evidence available.

Workflow 4: NMR Structural/Dynamics Data (BMRB)

Phase 1: Resolve target -> BMRB_search_by_keyword (protein name) or BMRB_search_by_sequence (exact sequence match)
         or, if you already have an NMR PDB entry -> BMRB_get_entries_by_pdb_id (cross-reference to the matching BMRB entry/entries)
         or BMRB_get_entries_by_uniprot (UniProt accession -> linked BMRB entries)
Phase 2: BMRB_get_entry(entry_id) -> full deposition: saveframes for entry_information, assigned chemical shifts,
         sample conditions, method. BMRB_get_entry_citation(entry_id) -> BibTeX citation for the deposition.
Phase 3: BMRB_get_validation(entry_id) -> AVS (assigned-value-set) analysis: per-residue/per-atom chemical-shift
         typing and assignment-quality scores -- use this before trusting a shift value, the same way
         PDBeValidation quality scores gate trust in an X-ray/cryo-EM structure.
Phase 4 (optional, slow): BMRB_search_chemical_shifts -> raw per-atom chemical-shift table for an entry
         (large response, 15-20s+ for popular entries -- only pull this when the actual shift values are
         needed, e.g. for a downstream chemical-shift-based dynamics or secondary-structure calculation).

Real example (verified live): PDB 1D3Z (an NMR ubiquitin structure) -> BMRB_get_entries_by_pdb_id returns BMRB entries 11505, 11547, 15047, ... (BLAST-matched by sequence, not a strict 1:1 PDB<->BMRB mapping -- expect several candidate entries and pick by title/method) -> BMRB_get_entry("11505") confirms title "Alternative structure of Ubiquitin" -> BMRB_get_validation("11505") returns the AVS chemical-shift-typing analysis for that deposition.

Tool note: BMRB_search_by_keyword's term parameter accepts a plain protein/molecule name (e.g. "ubiquitin", "calmodulin") -- not keyword, despite the tool name.

Workflow 5: Fold and Domain-Signature Classification (CATH + InterPro Member Databases)

CATH classifies a protein domain's 3D fold (Class/Architecture/Topology/Homologous-superfamily) and further groups domains into functionally-coherent FunFams within a superfamily. This is complementary to, not a replacement for, InterPro_get_protein_domains/Pfam_get_protein_annotations above: those two answer "what domains does this protein have," while CATH and the InterPro member-database tools here let you go the other direction — starting from a fold/superfamily/signature and finding everything that belongs to it (structures, domains, or the raw per-database signature catalog behind InterPro's integrated entries).

Phase 1: CATH_get_domain_summary(domain_id) -> C.A.T.H classification + residue count for one PDB-chain-domain
         (domain_id format: <pdb_id><chain><domain_number>, e.g. "1cukA01")
Phase 2: CATH_get_superfamily(superfamily_id) -> homologous-superfamily name + domain/family counts across all of CATH
Phase 3: CATH_list_funfams(superfamily_id) -> functional sub-families within that superfamily, ranked by member count
Phase 4: CATH_get_funfam(superfamily_id, funfam_number) -> detail for one specific FunFam

Real example (verified live): CATH_get_domain_summary(domain_id="1cukA01") -> cath_id: "2.40.50.140.116.1.1.1.1", superfamily 2.40.50.140 ("Nucleic acid-binding proteins", Mainly Beta) -> CATH_get_superfamily("2.40.50.140") -> 2,879 total domains in this superfamily -> CATH_list_funfams("2.40.50.140") -> 1,285 FunFams, top one "30S ribosomal protein S12" (6,057 members).

Tool note: CATH_get_superfamily takes superfamily_id, not cath_id — passing cath_id fails parameter validation even though the tool's own response echoes a cath_id field.

Phase 1: InterPro_list_member_databases() -> catalog of all 14 member databases (pfam, cathgene3d, ssf, panther,
         cdd, profile, smart, ncbifam, prosite, prints, hamap, pirsf, sfld, antifam) with entry counts
Phase 2: InterPro_list_member_signatures(member_database, page_size) -> browse that database's raw signature catalog,
         each entry showing its `integrated_interpro` cross-reference if InterPro has folded it into an integrated entry
Phase 3: InterPro_get_member_signature(member_database, accession) -> full detail for one signature (name, GO terms,
         protein/structure/taxa counts)
Phase 4: InterPro_get_structures_for_entry(interpro_id, page_size) -> real PDB structures (with experiment type and
         resolution) whose chains carry a given *integrated* InterPro entry

Real example (verified live): InterPro_get_member_signature(member_database="pfam", accession="PF00069") -> "Protein kinase domain", integrated_interpro: "IPR000719", 1,364,822 proteins / 5,477 structures / 36,542 taxa carry this signature -> InterPro_get_structures_for_entry(interpro_id="IPR000719") -> real PDB hits including kinase-inhibitor co-crystals (e.g. 10dj, Fyn kinase + saracatinib, 2.22Å) — a direct bridge from "this protein has a kinase domain" to "here are solved structures of that domain, several already in complex with a drug."

Tool note: InterPro_get_member_signature requires BOTH member_database and accession — the accession alone (e.g. PF00069) is not sufficient because the same-shaped accession could theoretically collide across member databases.

Workflow 5b: Whole-Protein Domain Architecture and Pfam Clans

Three more InterPro tools, keyed by Pfam accession/UniProt accession rather than the integrated InterPro ID used above — a different entry point for the same underlying database:

InterPro_get_protein_domain_architecture(accession) -> ALL Pfam domains on one protein at once, with
    exact residue start/end and the integrated InterPro ID for each -- the "what domains does this
    whole protein have, with coordinates" complement to InterPro_get_member_signature's "tell me about
    one specific signature" above
InterPro_get_structures_for_domain(pfam_accession, max_results) -> PDB structures containing a given
    Pfam domain -- the Pfam-accession-keyed sibling of InterPro_get_structures_for_entry(interpro_id)
    above; use whichever accession type (Pfam PFxxxxx vs integrated IPRxxxxxx) you already have,
    they answer the same question from the two different InterPro identifier namespaces
InterPro_get_clan_members(clan_accession, max_results) -> member Pfam families in a clan (Pfam's own
    superfamily grouping) -- distinct from CATH's superfamily/FunFam grouping in Workflow 5 above:
    CATH groups by solved 3D fold, Pfam clans group by sequence-profile relatedness; the two systems
    can (and often do) disagree on where the boundary of a "related family" sits

Real example (verified live, same protein as Workflow 1): InterPro_get_protein_domain_architecture(accession="P04637") (TP53) -> 4 real Pfam domains with exact coordinates: PF08563 "P53 transactivation motif" (6-30), PF18521 "Transactivation domain 2" (35-59), PF00870 "P53 DNA-binding domain" (100-288), PF07710 "P53 tetramerisation motif" (319-357) -- matches the tetramerisation/DNA-binding boundaries already used in this skill's other workflows. InterPro_get_clan_members(clan_accession="CL0016") -> real clan "PKinase" with 30+ member Pfam families.

Reliability warning (verified live, repeatedly): this InterPro endpoint family is intermittently flaky. The exact same call (InterPro_get_structures_for_domain(pfam_accession="PF00069")) returned "Not found in InterPro: PF00069" on two consecutive attempts, then succeeded on a third with no change to the request. InterPro_get_protein_domain_architecture showed the same pattern in reverse (failed via tu test's canned examples, succeeded via a fresh tu run moments later, on the identical accession). Treat a "Not found in InterPro" error from any tool in this cluster as inconclusive, not as proof the accession doesn't exist — retry 1-2 times before reporting an entry is missing.

Workflow 6: Intrinsic Disorder Assessment (MobiDB + DisProt + IUPred3)

These three tools answer the same underlying question — "is this region of the protein structured or disordered?" — with different evidence quality, from highest to lowest confidence:

Tier 1 (curated experimental evidence): DisProt_search(query) -> DisProt_get_entry(accession)
         -> real, literature-curated disordered-region boundaries with the experimental method that
            established them (NMR, circular dichroism, limited proteolysis, etc.)
Tier 2 (aggregated predictions + curation): MobiDB_get_protein(accession) / MobiDB_get_consensus(accession)
         -> merges DisProt curation with multiple computational predictors into one consensus view
            **currently unreachable, see Limitations below**
Tier 3 (single fast predictor, sequence-only): IUPred3_predict_disorder(accession, iupred_type=...)
         -> a real-time computed disorder score per residue; "long" = long disordered regions,
            "short" = short disordered segments, "anchor" = disorder that becomes ordered upon binding
            a partner (protein-binding-induced folding)

Real example (verified live): p53/P04637 — DisProt_get_entry("P04637") confirms curated disordered regions (DP00086, "Cellular tumor antigen p53"); IUPred3_predict_disorder(accession="P04637", iupred_type="long") returns a real per-residue disorder-score profile independently, useful for a quick check even without DisProt curation existing for a given protein.

When to use which: check DisProt first if you need citable, experimentally-validated boundaries. Use IUPred3 for any protein (curated or not) when you just need a fast disorder profile. Reach for MobiDB only once it is confirmed reachable again (see Limitations) — do not report a "no disorder data" conclusion based on a MobiDB timeout; that is a connectivity failure, not evidence of an ordered protein.

Workflow 7: Membrane Protein Structure (OPM + TopDB + PDBTM + ChannelsDB)

Phase 1: OPM_search_structures(query, limit) -> solved membrane-protein structures positioned in a lipid
         bilayer, with geometric/energetic properties: hydrophobic thickness, tilt angle, and
         transfer_energy_kcal_per_mol (more negative = more favorable membrane insertion)
Phase 2: TopDB_get_topology(identifier) -> curated per-segment topology (Inside/Membrane/Outside regions)
         for a named protein, cross-species; identifier is typically a TopDB/UniProt-style ID
         (e.g. "OPSD_HUMAN"), not a bare gene symbol
Phase 3: PDBTM_get_topology(pdb_id) -> structure-derived per-chain topology for one specific PDB entry:
         tm_type ("alpha"/"beta"/"non_tm"), num_tm_segments, is_membrane_embedded
Phase 4: ChannelsDB_get_channels_pdb(pdb_id) / ChannelsDB_get_channels_cofactor(pdb_id) -> detected
         channels/tunnels/pores through the structure (general access tunnels vs. cofactor-specific
         access tunnels) for a given PDB entry

Real example (verified live, cross-validated across all four tools on rhodopsin): OPM_search_structures(query="rhodopsin") finds real bacteriorhodopsin/archaerhodopsin family members with thickness/tilt data; TopDB_get_topology("OPSD_HUMAN") -> 7 transmembrane segments, reliability score 92.81; PDBTM_get_topology("1f88") -> chain A, tm_type: "alpha", num_tm_segments: 7 — the same helix count TopDB reported independently, a useful cross-check between curated (TopDB) and structure-derived (PDBTM) topology. ChannelsDB_get_channels_pdb on a real ion channel (1bl8, KcsA potassium channel) returns real annotated pore/tunnel data; not every PDB entry has ChannelsDB coverage — 1f88 (rhodopsin) returned "Protein with ID '1f88' not found in ChannelsDB" even though OPM/TopDB/PDBTM all have data for it, so a ChannelsDB miss does not mean the protein lacks a real pore.

Workflow 8: Enzyme Catalytic Mechanism (M-CSA)

M-CSA (Mechanism and Catalytic Site Atlas) curates the actual catalytic residues and reaction mechanism for enzymes with solved structures — distinct from BRENDA/kinetics data (rates/constants) and from generic active-site predictions (ProteinsPlus above, which is pocket-geometry-based, not mechanism-curated).

Phase 1: MCSA_search_enzymes(enzyme_name=... | ec_number=... | uniprot_id=...) -> candidate M-CSA entries
Phase 2: MCSA_get_entry(mcsa_id) -> full catalytic machinery: catalytic residues, mechanism steps,
         EC number(s), reference structure

Real example (verified live): MCSA_search_enzymes(enzyme_name="lysozyme") -> mcsa_id: 203, "lysozyme (glycosyl hydrolase 22 family)", EC 3.2.1.17, reference UniProt P00698 -> MCSA_get_entry(203) for the full mechanism detail.

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Workflow 2: Identify Binding Pocket Ligands

Phase 1: PDBe_get_structure_ligands + RCSBGraphQL_get_ligand_info + PDBe_KB_get_ligand_sites
Phase 2: ProteinsPlus_predict_binding_sites → druggability score, pocket residues
Phase 3: BindingDB_get_ligands_by_pdb/uniprot → Ki, Kd, IC50
Phase 4: RCSB_get_chemical_component for key ligands, or PDBe_get_compound_summary for
         the same 3-letter comp_id if you need InChI/InChIKey/SMILES/systematic names and
         cross-references (PubChem/DrugBank/EPA CompTox) rather than RCSB's structural fields

Filter artifacts: GOL, EDO, SO4, PEG, ACT, CL, NA. Keep cofactors (ATP, NAD, HEM) and catalytic metals (ZN, MG) if relevant.

Real example (verified live): PDBe_get_compound_summary({"comp_id":"ATP"}) -> formula C10H16N5O13P3, weight 507.181, InChIKey ZKHQWZAMYRWXGA-KQYNXXCUSA-N, cross-references including BRENDA and Probes And Drugs. PDBe_get_compound_summary({"comp_id":"HEM"}) -> formal_charge: null (a real schema mismatch, verified live: the tool's return_schema declares formal_charge as a non-nullable integer, but HEM's actual charge is reported as null — the call still succeeds and the rest of the data is correct, this is a documentation/schema gap, not a broken tool).

Gotcha (verified live, do not present as exhaustive): PDBe_get_compound_structures does not reliably return "all structures containing this compound" despite its description. Tested on ATP (which appears in thousands of real PDB structures — kinases, ATPases) and HEM (hemoglobins, cytochromes, peroxidases): both calls returned exactly ONE PDB entry each (1b0u for ATP, 3ia3 for HEM). Tracing the tool's implementation confirms why: when its primary per-compound structure list is empty, it silently falls back to the compound's first_observed_in field (which is inherently a single structure) and still labels that result pdb_entries. Treat a pdb_entries result from this tool as "one example structure containing this compound," not as a complete list — for an exhaustive structure search by ligand, use RCSBGraphQL_get_ligand_info or RCSBAdvSearch_search_structures instead.

Workflow 9: MD Simulation Trajectory Metadata (MDDB)

MDDB indexes 15,000+ molecular dynamics simulation trajectories (MoDEL, BioExcel, DESRES-ANTON, and community depositions) — metadata only (force field, temperature, ensemble, simulated time, frame count, trajectory size), not the trajectory files themselves. Use when a target already has (or you want to check whether it has) a published MD simulation, as a complement to the static structures the rest of this skill documents.

Phase 1: MDDB_search_projects(query, limit) -> candidate project accessions, by protein name or PDB id
Phase 2: MDDB_get_project(accession) -> full simulation parameters for one project

Real example (verified live): MDDB_search_projects({"query":"6M71","limit":5}) -> project MD-A001UA -> MDDB_get_project({"accession":"MD-A001UA"}) -> a real 10 microsecond DESRES-ANTON simulation of the SARS-CoV-2 nsp7-nsp8-nsp12 RNA polymerase complex (Amber ff99SB-ILDN, NPT ensemble, 310 K, 8,335 frames, ~2.5 GB) with a text description of a specific structural finding from the simulation (a disordered N-terminal region folding into a kinase-like fold during the run). Note total_simulated_time_ps is summed across all replicas listed under md_replica_count, not per-replica.

Workflow 3: Cross-Validate Drug Binding

Phase 1: Find co-crystal structures → filter for drug/analogs
Phase 2: BindingDB affinity data (Ki, Kd, IC50)
Phase 3: ProteinsPlus + PDBe-KB binding site characterization
Phase 4: PDBeValidation quality → binding site well-resolved?
Phase 5: AlphaFold + Foldseek structural comparison
Phase 6: GPCR-specific (if applicable) → active/inactive states, pharmacology, resistance mutations
Phase 7: Antibody-specific (if applicable) → epitope mapping
Phase 8: Evidence integration

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Tool Parameter Gotchas

Tool	Mistake	Correct
alphafold_get_prediction/summary	uniprot_id	qualifier
GPCRdb_get_protein	gene_name	protein
PDBeSIFTS_get_best_structures	gene symbol	uniprot_id (e.g., "P04637")
Foldseek_search_structure	mode="3diaa"	mode="tmalign"
SAbDab_search_structures	name	query or antigen
RCSB_get_chemical_component	ligand_id	comp_id
BMRB_search_by_keyword	keyword	term
CATH_get_superfamily	cath_id	superfamily_id
InterPro_get_member_signature	accession alone	member_database + accession (both required)
TopDB_get_topology	bare gene symbol	a TopDB/UniProt-style identifier (e.g. "OPSD_HUMAN")
PDBe_get_compound_structures	trusting pdb_entries as exhaustive	it falls back to a single first_observed_in example when the primary list is empty (verified live) — use RCSBGraphQL_get_ligand_info for a real exhaustive search

---

Evidence Grading

Tier	Confidence
T1	Co-crystal (<2.5A) + binding affinity data
T2	Experimental structure + computational prediction
T3	AlphaFold + pocket analysis + known ligand analogs
T4	Homology model or low-resolution only

Interpretation

Metric	High	Acceptable	Caution
Resolution	<2.0A (X-ray) / <3.0A (cryo-EM)	2.0-2.5A / 3.0-4.0A	>3.0A / >4.5A
R-free	<0.25	0.25-0.30	>0.30
AlphaFold pLDDT	>90	70-90	<70 (disordered)

DoGSiteScorer >0.6 = druggable; <0.4 = unlikely druggable. PISA assemblies should be cross-validated with SEC-MALS/native MS.

Limitations

• BindingDB: 60s+ for popular targets
• AlphaFold: lacks ligand context
• GPCRdb: Class A-F GPCRs only
• PDBePISA: operation is internal, not a public parameter
• BMRB: BMRB_get_entries_by_pdb_id is a BLAST-based sequence match, not a curated 1:1 PDB<->BMRB cross-reference -- a query can return several candidate entries (or none) for a real NMR PDB ID; BMRB_search_chemical_shifts is slow (15-20s+) for well-studied entries, only call it when raw shift values are actually needed
• MobiDB: MobiDB_get_protein and MobiDB_get_consensus were verified live (repeatedly, with a 90s timeout) to hang indefinitely against their configured endpoint (https://mobidb.org/api/download) -- confirmed independently via direct curl to the same host (20s with no response). This is an upstream connectivity issue, not a query-parameter mistake. Use DisProt (curated) or IUPred3 (fast predictor) instead until this is confirmed working again -- do not retry MobiDB with a longer timeout expecting it to resolve.
• ChannelsDB: coverage is per-PDB-entry, not universal -- a real membrane protein with confirmed topology elsewhere (OPM/TopDB/PDBTM) can still return "not found in ChannelsDB" for that specific PDB ID (verified live: 1f88 rhodopsin)
• InterPro domain-architecture cluster (InterPro_get_protein_domain_architecture/_get_structures_for_domain/_get_clan_members): the underlying InterPro API is intermittently flaky -- the identical query can 404 twice then succeed on a third attempt with no request change (verified live, repeatedly). A "Not found in InterPro" result is inconclusive on the first attempt; retry before concluding the accession/domain genuinely isn't in InterPro.
• PDBe_get_compound_summary: formal_charge is null for at least some neutral compounds (verified live: HEM) despite the tool's return_schema declaring it a non-nullable integer -- the call still succeeds with correct data otherwise, treat a null charge as "not reported as charged," not as a failure.
• PDBe_get_compound_structures: see the Workflow 2 gotcha above -- verified live to return only one example PDB entry even for ubiquitous ligands (ATP, HEM), not an exhaustive list.