---
title: PROTAC inputs and parameters
description: >-
  Warhead SMILES, E3 ligand structures, linker constraints, and scoring options
  for all PROTAC design tools.
tags:
  - protac
  - inputs
---

You provide warhead and E3 ligand SMILES, a full PROTAC structure, and POI/E3 structures; the choice of E3 system and linker length and flexibility constraints most shape which candidate degraders you get back.

## PROTAC inputs and parameters

## Common input formats

Most PROTAC tools accept one or more of these input types:

| Input | Format | Example | Accepted By |
|-------|--------|---------|-------------|
| Warhead SMILES | Valid SMILES string | `CC1=CC(=O)N(C2=CC=CC=C2)C1=O` | Linker Enumerate |
| E3 ligand SMILES | Valid SMILES string | `O=C1CCC(N2CC3=CC=CC=C3C2=O)C(=O)N1` | Linker Enumerate |
| Full PROTAC SMILES | Valid SMILES string | Warhead-linker-E3 ligand | Ternary Model, Degradation Score |
| POI structure | PDB ID or uploaded file | `3MXF` | Ternary Model |
| E3 structure | PDB ID or uploaded file | `4CI1` (CRBN), `4W9H` (VHL) | Ternary Model |
| E3 system | Enum string | `CRBN`, `VHL` | All tools |
| Job ID | UUID from previous run | `job_abc123` | Degradation Score (ternary input) |

## PROTAC Linker Enumerate parameters

| Parameter | Type | Required | Default | Description |
|-----------|------|----------|---------|-------------|
| `warhead_smiles` | string | Yes | -- | SMILES of the POI-binding warhead |
| `e3_ligand_smiles` | string | Yes | -- | SMILES of the E3 ligase recruiting ligand |
| `e3_system` | string | No | `"CRBN"` | E3 ligase system: `"CRBN"` or `"VHL"` |
| `min_linker_length` | integer | No | `4` | Minimum linker length in atoms (shortest path) |
| `max_linker_length` | integer | No | `12` | Maximum linker length in atoms (shortest path) |
| `scaffold_type` | string | No | `"diverse"` | Linker scaffold chemistry |
| `num_linkers` | integer | No | `50` | Number of linkers to generate (1-200) |
| `max_rotatable_bonds` | integer | No | `10` | Maximum rotatable bonds in the linker |
| `sa_threshold` | number | No | `5.0` | Maximum synthetic accessibility score (1-10, lower = easier) |

### Scaffold types

| Value | Chemistry | Description |
|-------|-----------|-------------|
| `"diverse"` | Mixed | Balanced mix of all scaffold types |
| `"peg"` | PEG | Polyethylene glycol chains (hydrophilic, flexible) |
| `"alkyl"` | Alkyl | Carbon chains (hydrophobic, flexible) |
| `"piperazine"` | Piperazine | Piperazine-containing (rigid, basic nitrogen) |
| `"triazole"` | Triazole | Click-chemistry-compatible (rigid, metabolically stable) |
| `"hybrid"` | Mixed rigid/flexible | Combines rigid and flexible elements |

### Linker length guidelines

| Length (atoms) | Typical Use |
|---------------|-------------|
| 4-6 | Short linkers, tight ternary complexes |
| 6-10 | Most common range, balanced flexibility |
| 10-14 | Long linkers, accommodates distant binding sites |
| > 14 | Very long, often poor drug-likeness |

## PROTAC Ternary Model parameters

| Parameter | Type | Required | Default | Description |
|-----------|------|----------|---------|-------------|
| `protac_smiles` | string | Yes | -- | SMILES of the full PROTAC molecule |
| `poi_structure` | string | Yes | -- | PDB ID or uploaded structure file for the protein of interest |
| `e3_structure` | string | No | Auto-selected | PDB ID or uploaded structure file for the E3 ligase |
| `e3_system` | string | No | `"CRBN"` | E3 ligase system: `"CRBN"` or `"VHL"` |
| `poi_binding_site` | string | No | Auto-detected | Residue range for POI binding site (e.g., `"A:100-120"`) |
| `num_conformers` | integer | No | `10` | Number of ternary complex conformers to sample (1-50) |
| `clash_tolerance` | number | No | `2.0` | Steric clash tolerance in Angstroms |

### Common E3 ligase structures

| E3 System | PDB ID | Description |
|-----------|--------|-------------|
| CRBN | `4CI1` | CRBN-DDB1 with pomalidomide |
| CRBN | `5FQD` | CRBN-DDB1 with lenalidomide |
| VHL | `4W9H` | VHL-ElonginB-ElonginC with VH032 |
| VHL | `5NVX` | VHL-ElonginB-ElonginC with MZ1 |

## PROTAC Degradation Score parameters

| Parameter | Type | Required | Default | Description |
|-----------|------|----------|---------|-------------|
| `protac_smiles` | string | Yes | -- | SMILES of the full PROTAC molecule |
| `e3_system` | string | No | `"CRBN"` | E3 ligase system: `"CRBN"` or `"VHL"` |
| `ternary_job_id` | string | No | -- | Job ID from a previous ternary model run (improves accuracy) |
| `poi_name` | string | No | -- | Target protein name for context (e.g., `"BRD4"`) |
| `cell_type` | string | No | `"general"` | Cell type context for expression-adjusted scoring |

### Cell type options

| Value | Description |
|-------|-------------|
| `"general"` | Expression-agnostic scoring |
| `"hek293"` | HEK293 cell expression levels |
| `"hela"` | HeLa cell expression levels |
| `"jurkat"` | Jurkat T-cell expression levels |
| `"mcf7"` | MCF-7 breast cancer cell expression levels |

## SMILES format requirements

### Warhead and E3 ligand SMILES

- Must be valid, sanitizable SMILES strings
- Should contain explicit attachment points where the linker connects (marked with `[*]` or left as open valences)
- Stereochemistry should be specified where relevant (e.g., VHL ligands require correct hydroxyproline stereochemistry)
- Maximum 200 heavy atoms per fragment

### Full PROTAC SMILES

- Must contain both the warhead and E3 ligand fragments connected by a linker
- Maximum 500 heavy atoms total
- Stereochemistry should be specified for E3 ligand and warhead stereocenters

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