ESM: Evolutionary Scale Modeling

# 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:**

```python
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:**

```python
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:**

```python
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):**

```python
# 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:**

```python
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:**

```python
# 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:**

```python
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.

```python
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.

```python
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)]
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:**

```bash
uv pip install esm
```

**With Flash Attention (recommended for faster inference):**

```bash
uv pip install esm
uv pip install flash-attn --no-build-isolation
```

**For Forge API access:**

```bash
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.