> ## Documentation Index
> Fetch the complete documentation index at: https://docs.boltz.bio/llms.txt
> Use this file to discover all available pages before exploring further.
# Constraints in Small-Molecule Design Projects
> How to use constraints to refine predicted apo structures before virtual screening.
Constraints work differently in **Small-Molecule Design Projects** compared to Sandbox.
In Small-Molecule Design Projects, constraints are applied only to the **predicted apo structure** of your target protein - not to individual molecules in your virtual screening libraries.
**Key Information:** They only modify the target protein's unbound structure.
If you need to test specific binding hypotheses (e.g., "does this warhead form a covalent bond?"), use **Sandbox** with constraints for those individual predictions. Then incorporate successful molecules into your Design Project.
***
## The Design Projects Workflow
Understanding where constraints fit in the Small-Molecule Design Projects workflow is critical:
Add your protein target sequence via FASTA, UniProt, RCSB PDB, or file import.
Boltz predicts the unbound (apo) structure of your target protein automatically.
Review the predicted apo structure. If there are structural issues—incorrect domain orientation, problematic loops, or conformational problems - you can add constraints to guide the model toward a better structure.
**This is the only step where constraints are used in Design Projects.**
Select residues that form your target binding site. Optionally provide probe molecules to help guide pocket prediction.
Screen your molecule libraries against the refined target structure. Individual molecules in these libraries cannot have constraints applied.
***
## When to Use Constraints in Design Projects
Constraints in Small-Molecule Design Projects serve a **quality control** function - fixing structural predictions before virtual screening begins. Use them when:
Multi-domain proteins predicted in non-native orientations that would block the intended binding site
Critical loops (e.g., DFG motif in kinases) predicted in inactive conformations when you need the active state
Allosteric or cryptic pockets that require specific residue positioning to remain accessible
Forcing a particular conformational state (open/closed, active/inactive) relevant to your screening hypothesis
**"Only use this target if the structure is predicted well."**
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## How to Apply Constraints to Apo Structures
During the **"Verify Unbound Structure"** step, you'll see the predicted apo structure with the option to add constraints.
### Adding Constraints
Click **"+ Add Constraint"** on the right panel to open the constraint editor. All three constraint types are available:
| Constraint Type | Use Case in Apo Structure Refinement |
| --------------- | ------------------------------------------------------------------------------------------ |
| **Bond** | Force disulfide bonds or covalent modifications not predicted correctly |
| **Contact** | Enforce proximity between domains or secondary structure elements |
| **Pocket** | Define where the binding pocket should form (alternative to manual pocket selection later) |
**Contact constraints** are most commonly used in Design Projects to fix domain-domain interfaces or enforce known structural features from experimental data (crystal structures, cryo-EM).
The constraint setup process is identical to Sandbox - refer to the [Setting Up Constraints](/user-guide/sandbox/Constraints/Setting-Up-Constraints) guide for detailed instructions.
***
## Best Practices for Design Projects
Review the apo structure without constraints first. Only add them if you see clear structural problems.
Base constraints on crystal structures, homology models, or known domain interfaces.
If unsure whether constraints will help, run a quick Sandbox prediction with and without constraints to compare.
After applying constraints and predicting the pocket structure, verify that the pocket is positioned correctly. Poor constraints can shift the pocket to the wrong location.
***
## Sandbox vs. Design Projects: When to Use Each
| Scenario | Recommended Workflow |
| -------------------------------------------------------- | ------------------------------------------------------------- |
| Testing a specific covalent warhead hypothesis | **Sandbox** with bond constraints |
| Screening 50,000 molecules against a kinase | **Design Projects** (no molecular constraints) |
| Fixing multi-domain protein orientation before screening | **Design Projects** with contact constraints on apo structure |
| Validating a molecular glue ternary complex | **Sandbox** with contact constraints |
| Targeting a cryptic allosteric pocket | **Design Projects** with pocket constraints on apo structure |
| Exploring different binding modes of one molecule | **Sandbox** without constraints (let model explore) |
***
## What's Next?
Detailed instructions for configuring bond, contact, and pocket constraints
Learn more about the Design Projects workflow
Complete guide to creating and refining target structures
Return to the Constraints overview for Sandbox workflows