In brief: ESM3 can condition on or generate structural information; ESMFold2 is purpose-built for structure prediction. The correct choice depends on whether you are designing a sequence, folding an existing sequence or evaluating a complex.
What ESM3 does
ESM3 models sequence, structure and function jointly as a generative system. It can generate missing structural information as part of a prompted design workflow. That capability does not mean every ESM3 output is a validated protein structure, nor does it make ESM3 the default folding tool for every task.
What ESMFold2 does
ESMFold2, released in the newer Biohub ecosystem, focuses on predicting high-resolution all-atom structures from biomolecular sequence inputs. Its public documentation describes optional multiple sequence alignment (MSA) input and capabilities relevant to protein complexes. It returns model predictions; conformational dynamics and cellular context still require other methods.
Compare by the research question
| Question | Suggested starting point |
|---|---|
| I need to propose candidates under partial constraints. | ESM3 |
| I need learned embeddings from sequences. | ESMC |
| I need a structural hypothesis for an existing sequence. | ESMFold2 |
| I need evidence of experimental function. | A relevant laboratory assay, not a model alone |
Assess uncertainty
Confidence metrics are useful diagnostics but can fail, particularly for out-of-distribution proteins and interfaces. Compare predictions with structures in the PDB where appropriate, inspect geometry and interfaces, and document whether the procedure used an MSA, templates or conditioning information. Structural similarity alone does not prove biological function.
Workflow recommendation
Start by specifying an observable endpoint (such as structure accuracy on a held-out benchmark), freeze evaluation criteria and run the recommended official notebook for the task. Avoid copying legacy ESM2 model names and assuming they invoke ESM3.
Primary sources and further reading
Editorial review: October 2026. This guide is educational. Model availability and APIs may change; confirm exact versions in the linked documentation. Generated structures and sequences require independent scientific validation.