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TPD / PROTAC

For a complete hands-on case, see TPD / PROTAC 5T35 case: BRD4-MZ1-VHL ternary complex.

Role

The TPD/PROTAC module supports POI-E3 ternary-complex modeling, warhead, E3 ligand, and linker design workflows.

Input asset chain

TPD is not a simple "protein in, protein out" workflow. DeepTernary inputs come from three source types:

  • POI protein asset: protein, prepared_protein, or a complex structure.
  • E3 ligase protein asset: protein, prepared_protein, or a complex structure.
  • Degrader / MGD ligand asset: ligand or prepared_ligand.

PROTAC jobs also require four auxiliary PDB assets:

  • POI-side binary ligand PDB.
  • E3-side binary ligand PDB.
  • POI-side mask PDB.
  • E3-side mask PDB.

These auxiliary PDB files are not new protein outputs. A binary ligand usually comes from the cocrystal small molecule in a POI-warhead or E3-ligand binary structure. A mask PDB is the substructure used to match the full PROTAC to the anchor/warhead atoms on each side. When users need to provide them, first create a TPD PDB asset from a PDB component in the protein-processing page, or upload a ligand/mask PDB asset in the ligand-processing page, then select that asset in the TPD page. The backend accepts asset IDs, not container file paths.

Auxiliary PDB selection rules:

  • Do not select a full protein or full cocrystal complex as a binary ligand or mask. A file that contains both protein chains and a ligand is not the file required by these fields.
  • Binary ligand PDB should be a ligand-only PDB extracted from a binary cocrystal structure, such as the warhead ligand from a POI-warhead structure or the E3 ligand from an E3-ligand structure.
  • Mask PDB is the substructure used to align each end of the full PROTAC. If the cocrystal ligand exactly matches the PROTAC end group, the mask can reuse the same PDB as the corresponding binary ligand. If the cocrystal ligand contains extra atoms outside the PROTAC end group, export only the shared anchor substructure.
  • Degrader / MGD ligand is the full PROTAC small molecule. Prefer a 3D SDF that RDKit can parse. If ligand preparation fails or logs show RDKit chirality, hydrogen, or bond-order errors, fix the full PROTAC file before changing protein assets.
  • If the uploaded full PROTAC already has reasonable 3D coordinates and users want to preserve them, enable "Disable ligand correction". This avoids DeepTernary trying to rebuild ligand coordinates from an RCSB {ligand_id}_ideal.sdf file.

POI, E3, and degrader/MGD are reusable upstream assets; binary ligand and mask PDB files are traceable auxiliary PDB assets. WA-DD can save, associate, and pass these files, but it does not decide which cocrystal ligand or mask substructure is scientifically correct for the user.

PLK1 PROTAC input-selection example

For a PLK1 PROTAC task, the usual asset sources are:

  1. Upload or prepare the POI protein in Protein Processing, remove the cocrystal ligand, and produce a prepared_protein.
  2. Upload or prepare the E3 ligase protein in Protein Processing, remove the cocrystal ligand, and produce a prepared_protein.
  3. Upload the full PROTAC / degrader molecule in Ligand Processing, producing a ligand or prepared_ligand asset.
  4. In the Protein Processing 3D component/chain view, select the HETATM ligand from the POI binary cocrystal structure and export it as a POI-side TPD PDB asset.
  5. Do the same for the E3 binary cocrystal ligand and export it as an E3-side TPD PDB asset.

When submitting DeepTernary, map the fields as follows:

TPD field Select this asset Do not select
POI protein structure POI prepared_protein with ligand removed Ligand-only PDB
E3 ligase structure E3 prepared_protein with ligand removed Ligand-only PDB
Degrader / MGD molecule Full PROTAC / degrader ligand asset POI warhead or E3 ligand fragment
POI binary ligand PDB Ligand-only PDB extracted from the POI binary structure Full POI protein or POI-ligand complex
E3 binary ligand PDB Ligand-only PDB extracted from the E3 binary structure Full E3 protein or E3-ligand complex
POI ligand mask PDB Ligand-only substructure used to align the POI end of the full PROTAC Full protein or full complex
E3 ligand mask PDB Ligand-only substructure used to align the E3 end of the full PROTAC Full protein or full complex

If the POI/E3 binary cocrystal ligand exactly matches the corresponding end group of the full PROTAC, the binary ligand PDB and ligand mask PDB can be the same ligand-only PDB. If the cocrystal ligand contains extra atoms outside the full PROTAC end group, export a separate mask substructure.

The validated PLK1 smoke task used this selection:

Field Example asset
POI protein structure 2YAC prepared
E3 ligase structure 4CI3 prepared
Degrader / MGD molecule PLK1-PROTAC
POI binary ligand PDB 2YAC 937 POI binary ligand PDB
E3 binary ligand PDB 4CI3 Y70 E3 binary ligand PDB
POI ligand mask PDB 2YAC_937_A501_lig1_mask
E3 ligand mask PDB 4CI3_Y70_B1429_lig2_mask

Assets such as 2YAC pdb_id or 4CI3 pdb_id must not be used in the binary ligand or mask fields. They contain protein chains, while these four DeepTernary auxiliary fields require ligand-only PDB files.

If the full PROTAC is already a reliable 3D SDF and the user wants to preserve its coordinates, enable "Disable ligand correction". The PLK1 example uses this mode.

Outputs and reuse

The reusable DeepTernary output asset is ternary_complex. It represents one ternary-complex prediction result and usually contains:

  • PDB ensemble: ternary-complex structures that can enter interaction analysis or be reused as complex structures.
  • Summary CSV: candidate conformations, seeds, and run summaries.
  • Run logs: useful for diagnosing input, GPU, or ligand-correction issues.

Downstream workflows should reference the ternary_complex asset itself instead of asking users to manually copy PDB or CSV file paths.

Result inspection

Recommended interaction order:

  1. Confirm the ternary_complex source chain: POI, E3, and ligand should match the intended inputs.
  2. Open or download the PDB ensemble to inspect the POI/E3/degrader relative conformation.
  3. Inspect the summary CSV for candidate count, seed details, and failures.
  4. For binding-interface interpretation, send the ternary-complex asset to the interaction-analysis page.

API / Automation

Job submission and result lookup reuse the unified automation model of project_id, asset_id, and job_id. Automation should persist and pass asset IDs, not container file paths.