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="
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.
- 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) )
- 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.
- 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) )
- 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)
- 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="
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 esmc-600m (36 layers) - Balanced performance esmc-6b (80 layers) - Maximum representation quality
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 High throughput: Use Forge API with batch executor Cost optimization: Use smaller models, implement caching strategies Installation
Basic installation:
uv pip install esm
With Flash Attention (recommended for faster inference):
uv pip install esm uv pip install flash-attn --no-build-isolation
For Forge API access:
uv pip install esm # SDK includes Forge client
No additional dependencies needed. Obtain Forge API token at https://forge.evolutionaryscale.ai
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/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 Forge Platform: https://forge.evolutionaryscale.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.