Enzyme Design

Design novel enzymes and ligand-binding proteins from a SMILES string — sequence, 3D structure, and automatic refolding validation.

MIP can design a novel protein from scratch for a target small molecule. Give it a SMILES string, and it generates an amino acid sequence together with a co-folded 3D structure, then independently refolds the design as a sanity check — all inside your chat.

Enzyme design is powered by DISCO (DIffusion for Sequence-structure CO-design), a diffusion model that jointly generates sequence and structure conditioned on a ligand. Designs are refolded with NVIDIA Boltz-2 and rendered with Mol*, the same viewer used by RCSB PDB.

Starting a design

Ask MIP to design a protein for a substrate or ligand:

• “Design an enzyme that binds caffeine”
• “Design a protein that catalyses cyclopropanation of styrene — use ethyl diazoacetate as the carbene source”
• “Design 3 scaffolds for this SMILES: CN1C=NC2=C1C(=O)N(C)C(=O)N2C”

MIP resolves the SMILES (pulling it from PubChem or ChEMBL if you give a common name), confirms parameters with you, estimates the GPU cost, and submits. A result card appears in chat while the design runs.

Input options

Parameter	What it does	Default
ligandSmiles	SMILES of the target substrate or ligand. Required.	—
proteinSequence	Partial sequence with - at positions to design. Enables motif scaffolding.	Fully masked 150-residue protein
dnaTarget	ACGT sequence for DNA-binding designs	None
rnaTarget	ACGU sequence for RNA-binding designs	None
effort	fast (100 diffusion steps, 2 recycles) or max (200 steps, 4 recycles)	max
numDesigns	Independent designs to generate (1–5)	3

Motif scaffolding

If you already know the catalytic residues you want to preserve, pass them inside proteinSequence. Fixed positions hold their amino acid, - positions are designed by DISCO.

• "----------S----------H----------D----------" pins a Ser/His/Asp triad and lets DISCO scaffold the rest.
• "MKGH----------------------------GGHM" fixes terminal residues and designs everything between.

The result card

When the job completes, a result card opens inline:

Design target

The ligand’s 2D structure, rendered from its canonical SMILES. Click Show SMILES to copy the string.

3D structure

An interactive Mol* viewer with the designed protein backbone and the co-folded ligand. Residues whose Cα lies within 5 Å of the ligand are highlighted. Multi-design jobs get a tab strip at the top so you can switch between seeds.

DISCO outputs backbone-only structures (N, Cα, C, O) — no sidechains. Highlighted residues are positional candidates near the ligand, not confirmed catalytic residues. Experimental characterisation is always required.

Structure composition

A compact bar chart of helix, sheet, and coil fractions computed from the backbone with Biotite.

Physical and chemical properties

Four sequence-derived numbers: molecular weight, isoelectric point, hydropathicity (GRAVY), and Guruprasad instability index.

A collapsible Sequence-derived heuristics section underneath shows charge at pH 7, extinction coefficient, aromatic fraction, and rough suggestions for ion-exchange buffer conditions. These are heuristics from the amino acid sequence, not predictions of expression behaviour.

Model confidence

DISCO’s native confidence scores — ranking score, inter-chain ipTM, and steric-clash flag when present.

Boltz-2 validation

Every design is automatically refolded with Boltz-2 to independently predict the structure from sequence and ligand. MIP then computes the backbone RMSD between DISCO’s structure and Boltz-2’s prediction.

RMSD	Verdict	Meaning
< 2.0 Å	PASS	The sequence encodes the intended fold (paper co-designability threshold)
2.0–3.0 Å	Marginal	Worth visual inspection; may be a loop difference
> 3.0 Å	Fail	The sequence refolds to something different — consider regenerating

Click Compare with Boltz-2 refold to open a side-by-side viewer with synchronised cameras. Rotating one structure rotates the other, which makes spotting real conformational differences much faster than reading the number alone.

Designed sequence

The amino acid sequence in monospace, color-coded by property group (hydrophobic, positive, negative, polar, Cys, Gly, Tyr). Residues with their Cα within 5 Å of the ligand are highlighted in emerald. Hover any residue to see its position and near-ligand status.

Downloading results

The result card toolbar provides:

• FASTA — the designed protein sequence as FASTA, ready for gene synthesis
• CIF / PDB — the full co-folded structure, openable in Mol*, PyMOL, or ChimeraX

Each design is also saved to your Datasets library so it is accessible from any future chat.

How it works

1. Validation — MIP parses your SMILES with openchemlib, rejects invalid input before any GPU spins up, and uses the canonical form so equivalent SMILES hit the dedup cache.
2. Submission — The DISCO input JSON is sent to a dedicated Cerebrium GPU (NVIDIA L40). Identical jobs submitted within 10 minutes return the existing result.
3. Design — DISCO runs effort diffusion steps with the configured number of recycles. Typical runtime is 15–60 minutes for effort=max on a 150–250 residue protein, scaling linearly with numDesigns.
4. Storage — Each design (CIF and FASTA) is uploaded to cloud storage.
5. Validation — A Boltz-2 refolding job is dispatched automatically. Results are joined back to the DISCO design card as they complete.
6. Billing — Charged at 10 credits per second of actual GPU time (including cold start), rounded up to the nearest minute.

Limits and guardrails

Parameter	Limit
Protein sequence length	1,000 residues (L40 GPU ceiling)
SMILES length	5,000 characters
DNA / RNA target length	10,000 bases
Concurrent GPU jobs per user	3
Minimum credit balance to start	5,000 credits
Boltz-2 validation cost	1,000 credits per design (skipped with a notification if the balance is too low)

MIP refuses, before any GPU is used, to design for chemical-weapon agents or scheduled precursors, controlled substances without a clear research context, known toxin scaffolds, or gain-of-function targets on select agents. If your request is legitimate research and MIP refuses, reach out to your institution’s biosafety officer and contact us.

When to use enzyme design vs structure prediction

Scenario	Recommended approach
You have a target protein and want its 3D structure	Use structure prediction
You have a small molecule and want a protein built for it	Use enzyme design
You have a known scaffold and want to alter a few residues	Use structure prediction with mutant comparison
You have a known active-site motif and want a new fold around it	Use enzyme design with motif scaffolding via proteinSequence

Enzyme design is iterative. Generate 3–5 designs, inspect the Boltz-2 RMSD per design, and prioritise the co-designable ones for experimental expression. Designs with RMSD above 3 Å are not reliable starting points — regenerate with a different seed or adjust the scaffold.

Designed enzymes are computational predictions, not proven catalysts. Plan for experimental characterisation — expression, purification, and activity assays — before treating a design as a working enzyme. The DISCO paper reports that one round of directed evolution on a designed enzyme can deliver several-fold activity improvements.