ESM: Evolutionary Scale Modeling

Overview

ESM provides state-of-the-art protein language models for understanding, generating, and designing proteins. This skill enables working with two model families: ESM3 for generative protein design across sequence, structure, and function, and ESM C for efficient protein representation learning and embeddings.

Core Capabilities

1. Protein Sequence Generation with ESM3

Generate novel protein sequences with desired properties using multimodal generative modeling.

When to use:

• Designing proteins with specific functional properties
• Completing partial protein sequences
• Generating variants of existing proteins
• Creating proteins with desired structural characteristics

Basic usage:

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

# Load model locally
model: ESM3InferenceClient = ESM3.from_pretrained("esm3-sm-open-v1").to("cuda")

# Create protein prompt
protein = ESMProtein(sequence="MPRT___KEND")  # '_' represents masked positions

# Generate completion
protein = model.generate(protein, GenerationConfig(track="sequence", num_steps=8))
print(protein.sequence)

For remote/cloud usage via Forge API:

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

# Connect to Forge
model = ESM3ForgeInferenceClient(model="esm3-medium-2024-08", url="https://forge.evolutionaryscale.ai", token="<token>")

# Generate
protein = model.generate(protein, GenerationConfig(track="sequence", num_steps=8))

See references/esm3-api.md for detailed ESM3 model specifications, advanced generation configurations, and multimodal prompting examples.

2. Structure Prediction and Inverse Folding

Use ESM3's structure track for structure prediction from sequence or inverse folding (sequence design from structure).

Structure prediction:

from esm.sdk.api import ESM3InferenceClient, ESMProtein, GenerationConfig

# Predict structure from sequence
protein = ESMProtein(sequence="MPRTKEINDAGLIVHSP...")
protein_with_structure = model.generate(
    protein,
    GenerationConfig(track="structure", num_steps=protein.sequence.count("_"))
)

# Access predicted structure
coordinates = protein_with_structure.coordinates  # 3D coordinates
pdb_string = protein_with_structure.to_pdb()

Inverse folding (sequence from structure):

# Design sequence for a target structure
protein_with_structure = ESMProtein.from_pdb("target_structure.pdb")
protein_with_structure.sequence = None  # Remove sequence

# Generate sequence that folds to this structure
designed_protein = model.generate(
    protein_with_structure,
    GenerationConfig(track="sequence", num_steps=50, temperature=0.7)
)

3. Protein Embeddings with ESM C

Generate high-quality embeddings for downstream tasks like function prediction, classification, or similarity analysis.

When to use:

• Extracting protein representations for machine learning
• Computing sequence similarities
• Feature extraction for protein classification
• Transfer learning for protein-related tasks

Basic usage:

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

# Load ESM C model
model = ESMC.from_pretrained("esmc-300m").to("cuda")

# Get embeddings
protein = ESMProtein(sequence="MPRTKEINDAGLIVHSP...")
protein_tensor = model.encode(protein)

# Generate embeddings
embeddings = model.forward(protein_tensor)

Batch processing:

# Encode multiple proteins
proteins = [
    ESMProtein(sequence="MPRTKEIND..."),
    ESMProtein(sequence="AGLIVHSPQ..."),
    ESMProtein(sequence="KTEFLNDGR...")
]

embeddings_list = [model.logits(model.forward(model.encode(p))) for p in proteins]

See references/esm-c-api.md for ESM C model details, efficiency comparisons, and advanced embedding strategies.

4. Function Conditioning and Annotation

Use ESM3's function track to generate proteins with specific functional annotations or predict function from sequence.

Function-conditioned generation:

from esm.sdk.api import ESMProtein, FunctionAnnotation, GenerationConfig

# Create protein with desired function
protein = ESMProtein(
    sequence="_" * 200,  # Generate 200 residue protein
    function_annotations=[
        FunctionAnnotation(label="fluorescent_protein", start=50, end=150)
    ]
)

# Generate sequence with specified function
functional_protein = model.generate(
    protein,
    GenerationConfig(track="sequence", num_steps=200)
)

5. Chain-of-Thought Generation

Iteratively refine protein designs using ESM3's chain-of-thought generation approach.

from esm.sdk.api import GenerationConfig

# Multi-step refinement
protein = ESMProtein(sequence="MPRT" + "_" * 100 + "KEND")

# Step 1: Generate initial structure
config = GenerationConfig(track="structure", num_steps=50)
protein = model.generate(protein, config)

# Step 2: Refine sequence based on structure
config = GenerationConfig(track="sequence", num_steps=50, temperature=0.5)
protein = model.generate(protein, config)

# Step 3: Predict function
config = GenerationConfig(track="function", num_steps=20)
protein = model.generate(protein, config)

6. Batch Processing with Forge API

Process multiple proteins efficiently using Forge's async executor.

from esm.sdk.forge import ESM3ForgeInferenceClient
import asyncio

client = ESM3ForgeInferenceClient(model="esm3-medium-2024-08", token="<token>")

# Async batch processing
async def batch_generate(proteins_list):
    tasks = [
        client.async_generate(protein, GenerationConfig(track="sequence"))
        for protein in proteins_list
    ]
    return await asyncio.gather(*tasks)

# Execute
proteins = [ESMProtein(sequence=f"MPRT{'_' * 50}KEND") for _ in range(10)]
resul