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:

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

# Same interface as local ESM3 — token from ESM_API_KEY (see Authentication)
model = esm.sdk.client("esm3-medium-2024-08", token=os.environ["ESM_API_KEY"])

# 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.

import os
import asyncio
import esm

client = esm.sdk.client("esm3-medium-2024-08", token=os.environ["ESM_API_KEY"])

# 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)]
results = asyncio.run(batch_generate(proteins))

See references/forge-api.md for detailed Forge API documentation, authentication, rate limits, and batch processing patterns.

Model Selection Guide

ESM3 Models (Generative):

• esm3-sm-open-v1 (1.4B) - Open weights, local usage, good for experimentation
• esm3-medium-2024-08 (7B) - Best balance of quality and speed (Forge only)
• esm3-large-2024-03 (98B) - Highest quality, slower (Forge only)

ESM C Models (Embeddings):

• esmc-300m (30 layers) - Lightweight, fast inference (open weights, local)
• esmc-600m (36 layers) - Balanced performance (open weights, local)
• esmc-6b-2024-12 (80 layers) - Maximum quality (Forge API; local 6B weights require Forge or SageMaker)

Selection criteria:

• Local development/testing: Use esm3-sm-open-v1 or esmc-300m
• Production quality: Use esm3-medium-2024-08 via Forge
• Maximum accuracy: Use esm3-large-2024-03 or esmc-6b-2024-12 via Forge
• High throughput: Use Forge API with batch executor
• Cost optimization: Use smaller models, implement caching strategies

Installation

Install from PyPI (esm on PyPI by EvolutionaryScale). Requires Python 3.12 (>=3.12,<3.13 for current releases).

Basic installation:

uv pip install "esm==3.2.3"

With Flash Attention (recommended for faster inference on NVIDIA GPUs):

uv pip install "esm==3.2.3"
uv pip install flash-attn --no-build-isolation

The Forge client ships with the esm package — no extra install for cloud inference.

Authentication

Forge API access requires an API key. Never hardcode tokens in scripts or commit them to version control.

1. Check whether ESM_API_KEY is already set in the environment.
2. If not, check a local .env for ESM_API_KEY only (do not load unrelated secrets).
3. If still missing, create a key at Forge (or Biohub developer console for newer ESMFold2 endpoints).

import os

token = os.environ["ESM_API_KEY"]  # raises KeyError if unset

esm.sdk.client() reads ESM_API_KEY automatically when token is omitted.

Biohub platform: EvolutionaryScale is migrating some services (including ESMFold2 structure prediction) to biohub.ai. SDK class names may still reference "Forge". See references/biohub-platform.md for ESMFold2 and Biohub-specific setup.

Common Workflows

For detailed examples and complete workflows, see references/workflows.md which includes:

• Novel GFP design with chain-of-thought
• Protein variant generation and screening
• Structure-based sequence optimization
• Function prediction pipelines
• Embedding-based clustering and analysis

References

This skill includes comprehensive reference documentation:

• references/esm3-api.md - ESM3 model architecture, API reference, generation parameters, and multimodal prompting
• references/esm-c-api.md - ESM C model details, embedding strategies, and performance optimization
• references/forge-api.md - Forge platform documentation, authentication, batch processing, and deployment
• references/biohub-platform.md - Biohub API migration, ESMFold2 structure prediction, and developer-console auth
• references/workflows.md - Complete examples and common workflow patterns

These references contain detailed API specifications, parameter descriptions, and advanced usage patterns. Load them as needed for specific tasks.

Best Practices

For generation tasks:

• Start with smaller models for prototyping (esm3-sm-open-v1)
• Use temperature parameter to control diversity (0.0 = deterministic, 1.0 = diverse)
• Implement iterative refinement with chain-of-thought for complex designs
• Validate generated sequences with structure prediction or wet-lab experiments

For embedding tasks:

• Batch process sequences when possible for efficiency
• Cache embeddings for repeated analyses
• Normalize embeddings when computing similarities
• Use appropriate model size based on downstream task requirements

For production deployment:

• Use Forge API for scalability and latest models
• Implement error handling and retry logic for API calls
• Monitor token usage and implement rate limiting
• Consider AWS SageMaker deployment for dedicated infrastructure

Resources and Documentation

• GitHub Repository: https://github.com/evolutionaryscale/esm (releases through v3.2.x; see also Biohub/esm for ESMFold2)
• Forge Platform: https://forge.evolutionaryscale.ai
• Biohub Platform: https://biohub.ai
• Scientific Paper: Hayes et al., Science (2025) - https://www.science.org/doi/10.1126/science.ads0018
• Blog Posts:
  • ESM3 Release: https://www.evolutionaryscale.ai/blog/esm3-release
  • ESM C Launch: https://www.evolutionaryscale.ai/blog/esm-cambrian
• Community: Slack community at https://bit.ly/3FKwcWd
• Model Weights: HuggingFace EvolutionaryScale organization

Responsible Use

ESM is designed for beneficial applications in protein engineering, drug discovery, and scientific research. Follow the Responsible Biodesign Framework (https://responsiblebiodesign.ai/) when designing novel proteins. Consider biosafety and ethical implications of protein designs before experimental validation.