ESM3 API Reference

Overview

ESM3 is a frontier multimodal generative language model that reasons over the sequence, structure, and function of proteins. It uses iterative masked language modeling to simultaneously generate across these three modalities.

Model Architecture

ESM3 Family Models:

Model ID	Parameters	Availability	Best For
`esm3-sm-open-v1`	1.4B	Open weights (local)	Development, testing, learning
`esm3-medium-2024-08`	7B	Forge API only	Production, balanced quality/speed
`esm3-large-2024-03`	98B	Forge API only	Maximum quality, research
`esm3-medium-multimer-2024-09`	7B	Forge API only	Protein complexes (experimental)

Key Features:

Simultaneous reasoning across sequence, structure, and function
Iterative generation with controllable number of steps
Support for partial prompting across modalities
Chain-of-thought generation for complex designs
Temperature control for generation diversity

Core API Components

ESMProtein Class

The central data structure representing a protein with optional sequence, structure, and function information.

Constructor:

python

from esm.sdk.api import ESMProtein

protein = ESMProtein(
    sequence="MPRTKEINDAGLIVHSP",           # Amino acid sequence (optional)
    coordinates=coordinates_array,          # 3D structure (optional)
    function_annotations=[...],             # Function labels (optional)
    secondary_structure="HHHEEEECCC",       # SS annotations (optional)
    sasa=sasa_array                        # Solvent accessibility (optional)
)

Key Methods:

python

# Load from PDB file
protein = ESMProtein.from_pdb("protein.pdb")

# Export to PDB format
pdb_string = protein.to_pdb()

# Save to file
with open("output.pdb", "w") as f:
    f.write(protein.to_pdb())

Masking Conventions:

Use _ (underscore) to represent masked positions for generation:

python

# Mask positions 5-10 for generation
protein = ESMProtein(sequence="MPRT______AGLIVHSP")

# Fully masked sequence (generate from scratch)
protein = ESMProtein(sequence="_" * 200)

# Partial structure (some coordinates None)
protein = ESMProtein(
    sequence="MPRTKEIND",
    coordinates=partial_coords  # Some positions can be None
)

GenerationConfig Class

Controls generation behavior and parameters.

Basic Configuration:

python

from esm.sdk.api import GenerationConfig

config = GenerationConfig(
    track="sequence",              # Track to generate: "sequence", "structure", or "function"
    num_steps=8,                  # Number of demasking steps
    temperature=0.7,              # Sampling temperature (0.0-1.0)
    top_p=None,                   # Nucleus sampling threshold
    condition_on_coordinates_only=False  # For structure conditioning
)

Parameter Details:

track: Which modality to generate
- "sequence": Generate amino acid sequence
- "structure": Generate 3D coordinates
- "function": Generate function annotations
num_steps: Number of iterative demasking steps
- Higher = slower but potentially better quality
- Typical range: 8-100 depending on sequence length
- For full sequence generation: approximately sequence_length / 2
temperature: Controls randomness
- 0.0: Fully deterministic (greedy decoding)
- 0.5-0.7: Balanced exploration
- 1.0: Maximum diversity
- Higher values increase novelty but may reduce quality
top_p: Nucleus sampling parameter
- Limits sampling to top probability mass
- Values: 0.0-1.0 (e.g., 0.9 = sample from top 90% probability mass)
- Use for controlled diversity without extreme sampling
condition_on_coordinates_only: Structure conditioning mode
- True: Condition only on backbone coordinates (ignore sequence)
- Useful for inverse folding tasks

ESM3InferenceClient Interface

The unified interface for both local and remote inference.

Local Model Loading:

python

from esm.models.esm3 import ESM3

# Load with automatic device placement
model = ESM3.from_pretrained("esm3-sm-open-v1").to("cuda")

# Or explicitly specify device
model = ESM3.from_pretrained("esm3-sm-open-v1").to("cpu")

Generation Method:

python

# Basic generation
protein_output = model.generate(protein_input, config)

# With explicit track specification
protein_output = model.generate(
    protein_input,
    GenerationConfig(track="sequence", num_steps=16, temperature=0.6)
)

Forward Pass (Advanced):

python

# Get raw model logits for custom sampling
protein_tensor = model.encode(protein)
output = model.forward(protein_tensor)
logits = model.decode(output)

Common Usage Patterns

1. Sequence Completion

Fill in masked regions of a protein sequence:

python

# Define partial sequence
protein = ESMProtein(sequence="MPRTK____LIVHSP____END")

# Generate missing positions
config = GenerationConfig(track="sequence", num_steps=12, temperature=0.5)
completed = model.generate(protein, config)

print(f"Original:  {protein.sequence}")
print(f"Completed: {completed.sequence}")

2. Structure Prediction

Predict 3D structure from sequence:

python

# Input: sequence only
protein = ESMProtein(sequence="MPRTKEINDAGLIVHSPQWFYK")

# Generate structure
config = GenerationConfig(track="structure", num_steps=len(protein.sequence))
protein_with_structure = model.generate(protein, config)

# Save as PDB
with open("predicted_structure.pdb", "w") as f:
    f.write(protein_with_structure.to_pdb())

3. Inverse Folding

Design sequence for a target structure:

python

# Load target structure
target = ESMProtein.from_pdb("target.pdb")

# Remove sequence, keep structure
target.sequence = None

# Generate sequence that folds to this structure
config = GenerationConfig(
    track="sequence",
    num_steps=50,
    temperature=0.7,
    condition_on_coordinates_only=True
)
designed = model.generate(target, config)

print(f"Designed sequence: {designed.sequence}")

4. Function-Conditioned Generation

Generate protein with specific function:

python

from esm.sdk.api import FunctionAnnotation

# Specify desired function
protein = ESMProtein(
    sequence="_" * 150,
    function_annotations=[
        FunctionAnnotation(
            label="enzymatic_activity",
            start=30,
            end=90
        )
    ]
)

# Generate sequence with this function
config = GenerationConfig(track="sequence", num_steps=75, temperature=0.6)
functional_protein = model.generate(protein, config)

5. Multi-Track Generation (Chain-of-Thought)

Iteratively generate across multiple tracks:

python

# Start with partial sequence
protein = ESMProtein(sequence="MPRT" + "_" * 100)

# Step 1: Complete sequence
protein = model.generate(
    protein,
    GenerationConfig(track="sequence", num_steps=50, temperature=0.6)
)

# Step 2: Predict structure for completed sequence
protein = model.generate(
    protein,
    GenerationConfig(track="structure", num_steps=50)
)

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

print(f"Final sequence: {protein.sequence}")
print(f"Functions: {protein.function_annotations}")

6. Variant Generation

Generate multiple variants of a protein:

python

import numpy as np

base_sequence = "MPRTKEINDAGLIVHSPQWFYK"
variants = []

for i in range(10):
    # Mask random positions
    seq_list = list(base_sequence)
    mask_indices = np.random.choice(len(seq_list), size=5, replace=False)
    for idx in mask_indices:
        seq_list[idx] = '_'

    protein = ESMProtein(sequence=''.join(seq_list))

    # Generate variant
    variant = model.generate(
        protein,
        GenerationConfig(track="sequence", num_steps=8, temperature=0.8)
    )
    variants.append(variant.sequence)

print(f"Generated {len(variants)} variants")

Advanced Topics

Temperature Scheduling

Vary temperature during generation for better control:

python

def generate_with_temperature_schedule(model, protein, temperatures):
    """Generate with decreasing temperature for annealing."""
    current = protein
    steps_per_temp = 10

    for temp in temperatures:
        config = GenerationConfig(
            track="sequence",
            num_steps=steps_per_temp,
            temperature=temp
        )
        current = model.generate(current, config)

    return current

# Example: Start diverse, end deterministic
result = generate_with_temperature_schedule(
    model,
    protein,
    temperatures=[1.0, 0.8, 0.6, 0.4, 0.2]
)

Constrained Generation

Preserve specific regions during generation:

python

# Keep active site residues fixed
def mask_except_active_site(sequence, active_site_positions):
    """Mask everything except specified positions."""
    seq_list = ['_'] * len(sequence)
    for pos in active_site_positions:
        seq_list[pos] = sequence[pos]
    return ''.join(seq_list)

# Define active site
active_site = [23, 24, 25, 45, 46, 89]
constrained_seq = mask_except_active_site(original_sequence, active_site)

protein = ESMProtein(sequence=constrained_seq)
result = model.generate(protein, GenerationConfig(track="sequence", num_steps=50))

Secondary Structure Conditioning

Use secondary structure information in generation:

python

# Define secondary structure (H=helix, E=sheet, C=coil)
protein = ESMProtein(
    sequence="_" * 80,
    secondary_structure="CCHHHHHHHEEEEECCCHHHHHHCC" + "C" * 55
)

# Generate sequence with this structure
result = model.generate(
    protein,
    GenerationConfig(track="sequence", num_steps=40, temperature=0.6)
)

Performance Optimization

Memory Management

For large proteins or batch processing:

python

import torch

# Clear CUDA cache between generations
torch.cuda.empty_cache()

# Use half precision for memory efficiency
model = ESM3.from_pretrained("esm3-sm-open-v1").to("cuda").half()

# Process in chunks for very long sequences
def chunk_generate(model, long_sequence, chunk_size=500):
    chunks = [long_sequence[i:i+chunk_size]
              for i in range(0, len(long_sequence), chunk_size)]
    results = []

    for chunk in chunks:
        protein = ESMProtein(sequence=chunk)
        result = model.generate(protein, GenerationConfig(track="sequence"))
        results.append(result.sequence)

    return ''.join(results)

Batch Processing Tips

When processing multiple proteins:

Sort by sequence length for efficient batching
Use padding for similar-length sequences
Process on GPU when available
Implement checkpointing for long-running jobs
Use Forge API for large-scale processing (see forge-api.md)

Error Handling

python

try:
    protein = model.generate(protein_input, config)
except ValueError as e:
    print(f"Invalid input: {e}")
    # Handle invalid sequence or structure
except RuntimeError as e:
    print(f"Generation failed: {e}")
    # Handle model errors
except torch.cuda.OutOfMemoryError:
    print("GPU out of memory - try smaller model or CPU")
    # Fallback to CPU or smaller model

Model-Specific Considerations

esm3-sm-open-v1:

Suitable for development and testing
Lower quality than larger models
Fast inference on consumer GPUs
Open weights allow fine-tuning

esm3-medium-2024-08:

Production quality
Good balance of speed and accuracy
Requires Forge API access
Recommended for most applications

esm3-large-2024-03:

State-of-the-art quality
Slowest inference
Use for critical applications
Best for novel protein design

Citation

If using ESM3 in research, cite:

Hayes, T. et al. (2025). Simulating 500 million years of evolution with a language model.
Science. DOI: 10.1126/science.ads0018