Table of Contents

1. Installation
2. ESM C
3. ESM 3
4. Responsible Development
5. License

Installation

To get started with ESM, install the library using pip:

pip install esm

ESM C

ESM Cambrian is a parallel model family to our flagship ESM3 generative models. While ESM3 focuses on controllable generation of proteins for therapeutic and many other applications, ESM C focuses on creating representations of the underlying biology of proteins.

ESM C comes with major performance benefits over ESM2. The 300M parameter ESM C delivers similar performance to ESM2 650M with dramatically reduced memory requirements and faster inference. The 600M parameter ESM C rivals the 3B parameter ESM2 and approaches the capabilities of the 15B model, delivering frontier performance with far greater efficiency. The 6B parameter ESM C sets a new benchmark, outperforming the best ESM2 models by a wide margin.

ESM C models are available immediately for academic and commercial use under a new license structure designed to promote openness and enable scientists and builders. You can find the high level take-away of the license structure in the Licenses section of this page, and the full license structure in the LICENSE.md file.

You can use the following guides to start using ESM C models today, either running the model locally, the Forge API and AWS SageMaker.

Using ESM C 300M and 600M via GitHub

ESM C model weights are stored on the HuggingFace hub under https://huggingface.co/EvolutionaryScale/.

from esm.models.esmc import ESMC
from esm.sdk.api import ESMProtein, LogitsConfig

protein = ESMProtein(sequence="AAAAA")
client = ESMC.from_pretrained("esmc_300m").to("cuda") # or "cpu"
protein_tensor = client.encode(protein)
logits_output = client.logits(
   protein_tensor, LogitsConfig(sequence=True, return_embeddings=True)
)
print(logits_output.logits, logits_output.embeddings)

Using ESM C 6B via Forge API

ESM C models, including ESMC 6B, are accessible via EvolutionaryScale Forge. You can request access and utilize these models through forge.evolutionaryscale.ai, as demonstrated in the example below.

from esm.sdk.forge import ESM3ForgeInferenceClient
from esm.sdk.api import ESMProtein, LogitsConfig

# Apply for forge access and get an access token
forge_client = ESM3ForgeInferenceClient(model="esmc-6b-2024-12", url="https://forge.evolutionaryscale.ai", token="<your forge token>")
protein = ESMProtein(sequence="AAAAA")
protein_tensor = forge_client.encode(protein)
logits_output = forge_client.logits(
   protein_tensor, LogitsConfig(sequence=True, return_embeddings=True)
)
print(logits_output.logits, logits_output.embeddings)

Using ESM C 6B via SageMaker

ESM C models are also available on Amazon SageMaker. They function similarly to the ESM3 model family, and you can refer to the sample notebooks provided in this repository for examples.

After creating the endpoint, you can create a sagemaker client and use it the same way as a forge client. They share the same API.

sagemaker_client = ESM3SageMakerClient(
   endpoint_name=SAGE_ENDPOINT_NAME, model=<model_name>
)

ESM 3

ESM3 is a frontier generative model for biology, able to jointly reason across three fundamental biological properties of proteins: sequence, structure, and function. These three data modalities are represented as tracks of discrete tokens at the input and output of ESM3. You can present the model with a combination of partial inputs across the tracks, and ESM3 will provide output predictions for all the tracks.

ESM3 is a generative masked language model. You can prompt it with partial sequence, structure, and function keywords, and iteratively sample masked positions until all positions are unmasked. This iterative sampling is what the .generate() function does.

The ESM3 architecture is highly scalable due to its transformer backbone and all-to-all reasoning over discrete token sequences. At its largest scale, ESM3 was trained with 1.07e24 FLOPs on 2.78 billion proteins and 771 billion unique tokens, and has 98 billion parameters. Learn more by reading the blog post and the pre-print (Hayes et al., 2024).

Here we present esm3-open-small. With 1.4B parameters it is the smallest and fastest model in the family. ESM3-open is available under the Cambrian non-commercial license agreement, as outlined in LICENSE.md (note: updated with ESM C release). Visit our Discussions page to get in touch, provide feedback, ask questions or share your experience with ESM3!

Quickstart for ESM3-open

pip install esm

In order to download the weights, we require users to accept our non-commercial license. The weights are stored on HuggingFace Hub under HuggingFace/EvolutionaryScale/esm3. Please create an account and accept the license.

from huggingface_hub import login
from esm.models.esm3 import ESM3
from esm.sdk.api import ESM3InferenceClient, ESMProtein, GenerationConfig

# Will instruct you how to get an API key from huggingface hub, make one with "Read" permission.
login()

# This will download the model weights and instantiate the model on your machine.
model: ESM3InferenceClient = ESM3.from_pretrained("esm3-open").to("cuda") # or "cpu"

# Generate a completion for a partial Carbonic Anhydrase (2vvb)
prompt = "___________________________________________________DQATSLRILNNGHAFNVEFDDSQDKAVLKGGPLDGTYRLIQFHFHWGSLDGQGSEHTVDKKKYAAELHLVHWNTKYGDFGKAVQQPDGLAVLGIFLKVGSAKPGLQKVVDVLDSIKTKGKSADFTNFDPRGLLPESLDYWTYPGSLTTPP___________________________________________________________"
protein = ESMProtein(sequence=prompt)
# Generate the sequence, then the structure. This will iteratively unmask the sequence track.
protein = model.generate(protein, GenerationConfig(track="sequence", num_steps=8, temperature=0.7))
# We can show the predicted structure for the generated sequence.
protein = model.generate(protein, GenerationConfig(track="structure", num_steps=8))
protein.to_pdb("./generation.pdb")
# Then we can do a round trip design by inverse folding the sequence and recomputing the structure
protein.sequence = None
protein = model.generate(protein, GenerationConfig(track="sequence", num_steps=8))
protein.coordinates = None
protein = model.generate(protein, GenerationConfig(track="structure", num_steps=8))
protein.to_pdb("./round_tripped.pdb")

Congratulations, you just generated your first proteins with ESM3! Let's explore some more advanced prompting with the help of our notebooks and scripts.

generate.ipynb will walk through two prompting examples (scaffolding and secondary structure editing) using the open model:

gfp_design.ipynb will walk through the more complex generation procedure we used to design esmGFP:

We also provide example scripts that show common workflows under examples/:

• local_generate.py shows how simple and elegant common tasks are: it shows folding, inverse folding and chain of thought generation, all by calling just model.generate() for iterative decoding.
• seqfun_struct.py shows direct use of the model as a standard pytorch model with a simple model forward call.

Forge: Access to larger ESM3 models

You can apply for beta access to the full family of larger and higher capability ESM3 models at EvolutionaryScale Forge.

We encourage users to interact with the Forge API through the python esm library instead of the command line. The python interface enables you to interactively load proteins, build prompts, and inspect generated proteins with the ESMProtein and config classes used to interact with the local model.

In any example script try to replace a local ESM3 model with a Forge API client:

# Instead of loading the model locally on your machine:
model: ESM3InferenceClient = ESM3.from_pretrained("esm3_sm_open_v1").to("cuda") # or "cpu"
# just replace the line with this:
model: ESM3InferenceClient = esm.sdk.client("esm3-medium-2024-08", token="<your forge token>")
# and now you're interfacing with the model running on our remote servers.
...

and the exact same code will work. This enables a seamless transition from smaller and faster models, to our large 98B protein language models for protein design work.

Responsible Development

EvolutionaryScale is a public benefit company. Our mission is to develop artificial intelligence to understand biology for the benefit of human health and society, through partnership with the scientific community, and open, safe, and responsible research. Inspired by the history of our field as well as new principles and recommendations, we have created a Responsible Development Framework to guide our work towards our mission with transparency and clarity.

The core tenets of our framework are

• We will communicate the benefits and risks of our research
• We will proactively and rigorously evaluate the risk of our models before public deployment
• We will adopt risk mitigation strategies and precautionary guardrails
• We will work with stakeholders in government, policy, and civil society to keep them informed

With this in mind, we have performed a variety of mitigations for esm3-sm-open-v1, detailed in our paper

Licenses

The code and model weights of ESM3 and ESM C are available under a mixture of non-commercial and more permissive licenses, fully outlined in LICENSE.md.