Overview

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.

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When Should You Use Constraints?

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. 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.

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Contact Constraints

Define distance restraints between atoms or residues. 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).

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Pocket Constraints

Define binding site residues where a ligand/chain should bind. 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.

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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.

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What’s Next?