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Documentation Index

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Constraints allow you to incorporate experimental knowledge or structural hypotheses directly into Boltz predictions. While standard predictions to well-defined binding sites work without constraints, they become essential for covalent attachments, cryptic pockets, and ambiguous binding modes.
For well-characterized binding interactions (such as reversible inhibitors at orthosteric sites, or known protein-protein interfaces), constraints are optional.The model will find the binding site automatically.

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When Should You Use Constraints?

Covalent Attachments

Specify specific atom-atom covalent bonds

Cryptic Pockets

Direct binders to non-obvious or allosteric binding sites

Molecular Glues

Enforce proximity between biomolecular chains or domains
Constraints are most valuable when you have prior structural knowledge—SAR data showing a covalent attachment, a crystal structure revealing an allosteric pocket, or biochemical evidence of a biomolecular interaction.

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Three Types of Constraints

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Bond Constraints

Define covalent bonds between specific atoms.
PropertyDescription
Use CaseCovalent bonds (acrylamide warheads, nitrile warheads, disulfide bridges)
Inputs RequiredChain + Residue + Atom for both bonding partners
Model BehaviorHard constraint—these atoms MUST form a bond
Bond constraints are essential for predicting structures with covalent attachments between any biomolecular components—such as covalent inhibitors (e.g., EGFR inhibitors targeting Cys797), disulfide bonds, or peptide cyclization.

Example: Covalent Inhibitors

Step-by-step guide for modeling covalent bonds

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Contact Constraints

Define distance restraints between atoms or residues.
PropertyDescription
Use CaseKnown interaction sites
Inputs RequiredTwo entities + maximum distance (4-20 Å)
Model BehaviorPredicts a structure using the given information as a constraint
Contact constraints help when you know two regions should interact. They’re useful for enforcing proximity between any pair of biomolecules—proteins, ligands, DNA, RNA, or combinations thereof (e.g., molecular glues bridging protein chains, or ligand-DNA contacts).

Example: Molecular Glues

Guide multi-protein assemblies with contact restraints

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Pocket Constraints

Define binding site residues where a ligand/chain should bind.
PropertyDescription
Use CaseCryptic pockets, allosteric sites, ambiguous binding modes
Inputs RequiredSet of residues + which chain should bind
Model BehaviorDirects binder chain toward specified pocket region
Pocket constraints are critical when your target has multiple potential binding sites and you want to focus on a specific one—such as an allosteric site distinct from the orthosteric pocket. The binder chain can also be a polymer, for example, to specify the epitope that an antibody binds to on the antigen.

Example: Cryptic Pockets

Target specific binding regions with pocket constraints

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Using Constraints in Design Projects

Constraints become even more powerful in Design Projects, where they guide virtual screening campaigns and iterative design cycles. You can apply the same constraint logic to entire libraries of compounds, ensuring all predictions respect your structural requirements.
While constraints can also be used to test multiple hypotheses, pay attention: overly restrictive constraints can force the model into unrealistic conformations.

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What’s Next?

Setting Up Constraints

Detailed instructions for configuring each constraint type

Constraints in Design Projects

Apply constraints across virtual screening campaigns