ESM Protein Language Models

The ESM line is maintained at github.com/Biohub/esm (Chan Zuckerberg Biohub, MIT license; the older evolutionaryscale/esm URL redirects here). The current generation ships three artifacts: ESM C (language model), ESMFold2 (structure prediction), and ESM Atlas (a map of predicted structures). Weights are on huggingface.co/biohub; the hosted API is at biohub.ai.

This skill covers ESM C, ESMFold2, and legacy ESM2. ESM3 is not covered because its open weights are non-commercial.

Which model to use

Task	Model
Embeddings, PLL, mutation scoring	ESM C (ESMC-6B), or ESM2 for a lighter run
Complex structure prediction	ESMFold2
High-throughput single-sequence folding	ESMFold2 fast mode
Binder design	ESMFold2 inversion (see below), or the mosaic / bindcraft skills
Variant effect / zero-shot scoring	ESM C or ESM2

Prerequisites

Requirement	Minimum	Recommended
Python	3.10+	3.11
PyTorch	2.0+	Latest
CUDA	12.0+	12.1+
GPU VRAM	24GB (ESM2 / small ESMC)	80GB (ESMC-6B, ESMFold2)

ESM C: embeddings and scoring

ESM C is the successor to ESM2. It improves long-range structural understanding as model scale grows and is the default choice for embeddings, pseudo-log-likelihood, and mutation-effect scoring.

Python (Hugging Face)

from transformers import AutoModelForMaskedLM, AutoTokenizer
import torch

model_id = "biohub/ESMC-6B"
tok = AutoTokenizer.from_pretrained(model_id)
model = AutoModelForMaskedLM.from_pretrained(
    model_id, output_hidden_states=True, torch_dtype=torch.bfloat16
).eval().cuda()

batch = tok(["MKTAYIAKQRQISFVK..."], return_tensors="pt").to("cuda")
with torch.no_grad():
    out = model(**batch)

logits = out.logits                      # for PLL / mutation scoring
embeddings = out.hidden_states[-1]       # per-residue representations

Install the package with pip install esm@git+https://github.com/Biohub/esm.git@main.

Hosted API

from esm.sdk import esmc_client
from esm.sdk.api import ESMProtein, LogitsConfig

model = esmc_client(model="esmc-600m-2024-12", url="https://biohub.ai", token="<API token>")
tensor = model.encode(ESMProtein(sequence="MKTAYIAKQRQISFVK..."))
out = model.logits(tensor, LogitsConfig(sequence=True, return_embeddings=True))

ESMC-6B has open weights; esmc-600m is the smaller API model. For mutation scoring and fine-tuning, see the esmc_mutation_scoring and esmc_finetune notebooks under cookbook/tutorials.

ESMFold2: complex structure prediction

ESMFold2 is built on ESMC-6B with a diffusion structure head. Unlike the original ESMFold, it predicts complexes (protein, DNA, ligand, and modified residues), takes an optional MSA, and has a single-sequence fast mode for high-throughput screening. It is validated for protein-protein interaction design and leads DockQ pass-rate on Foldbench protein-protein and antibody-antigen complexes.

Modal (biomodals)

printf '>protein|A\nMKTAYIAKQRQISFVK...\n' > target.faa
uv run --with modal modal run modal_esmfold2.py --input-faa target.faa

The FASTA header tags protein|, dna|, rna|, and ligand| (SMILES) let you fold complexes. GPU defaults to A100-40GB (set with MODAL_GPU).

Python (local weights)

from transformers.models.esmfold2.modeling_esmfold2 import ESMFold2Model
from esm.models.esmfold2 import ProteinInput, StructurePredictionInput, ESMFold2InputBuilder

model = ESMFold2Model.from_pretrained("biohub/ESMFold2").cuda().eval()
spi = StructurePredictionInput(sequences=[ProteinInput(id="A", sequence="BINDER_SEQ")])
result = ESMFold2InputBuilder().fold(model, spi, num_loops=20, num_sampling_steps=100)
# result.plddt, result.ptm, result.iptm, result.complex.to_mmcif()

For single-sequence high-throughput folding, the fast variant is the SDK model string esmfold2-fast-2026-05 (HF repo biohub/ESMFold2-Fast). ESMFold2 is one option for complex validation alongside boltz and chai; ranking a shortlist across more than one predictor is more reliable than trusting a single model.

Binder design by inverting ESMFold2

The binder_design cookbook runs gradient optimization through ESMFold2 (a BindCraft-style loop) with an ESMC language-model term for sequence plausibility. The published protocol is validated in the lab to nanomolar affinity across five targets and supports both minibinders and antibody-derived scFvs with framework scaffolds.

biomodals wraps this as modal_esmfold2_binder_design.py:

uv run --with modal modal run modal_esmfold2_binder_design.py \
  --target-name pd-l1 --binder-name minibinder

• Targets: presets cd45, ctla4, egfr, pd-l1, pdgfr, or pass --target-sequence.
• Binders: presets minibinder and antibody frameworks (for example trastuzumab_framework_vhvl), or pass --binder-sequence with # for designable positions. Use --is-antibody for scFv designs.
• Rank candidates by ipTM, filter minibinders to pI below 6, then validate the top shortlist with boltz or chai and rank with ipsae.

Adaptyv's own tests of these models showed ESMFold2-inversion binder design costing about $0.85 per accepted design, averaged across 7 targets.

For a framework that composes ESMFold2 with other predictors in one objective, use the mosaic skill.

ESM2 (legacy)

ESM2 still works well for quick embeddings and PLL when ESMC-6B is too large for the available GPU.

import torch, esm
model, alphabet = esm.pretrained.esm2_t33_650M_UR50D()
bc = alphabet.get_batch_converter()
model = model.eval().cuda()
_, _, toks = bc([("seq1", "MKTAYIAKQRQISFVK...")])
with torch.no_grad():
    rep = model(toks.cuda(), repr_layers=[33])["representations"][33]

Model	Parameters	Use
esm2_t12_35M	35M	Fast screening
esm2_t33_650M	650M	Standard embeddings/PLL
esm2_t36_3B	3B	Highest-quality ESM2

PLL interpretation

PLL (pseudo-log-likelihood) scores how natural a sequence looks to the model. Higher is more natural. Designed sequences often score lower than natural ones, so treat PLL as a soft filter, not a hard cutoff.

Normalized PLL	Interpretation
> 0.2	Very natural
0.0 to 0.2	Natural-like
-0.5 to 0.0	Acceptable
< -0.5	May be unnatural

Troubleshooting

Issue	Cause	Fix
CUDA out of memory	ESMC-6B / ESMFold2 too large	Use ESMC-600m API, ESM2, or an 80GB GPU
Wrong layer for embeddings	Layer index mismatch	Use the last hidden state (layer 33 for ESM2-650M)
Invalid amino acid	Non-standard residue	Check for non-canonical characters
Slow ESMFold2 on many designs	Full MSA mode	Use esmfold2-fast-2026-05 single-sequence mode

---

Next: Validate structures with boltz or chai, rank with ipsae, then filter with protein-qc.