iterative_alignment_experiment_structure/sample_esm_first_round.py

import os
import torch
import numpy as np
import pandas as pd
import h5py
import re
from omegaconf import OmegaConf
import h5py
import lightning as L
from pera.nn import BidirectionalModel, sample_components_from_bidirectional_transformer, sample_perturbations, sample_embedding_perturbations
from esm.tokenization.sequence_tokenizer import EsmSequenceTokenizer
from Bio.Seq import Seq
from Bio.PDB import PDBList, PDBParser, is_aa

device = torch.device("cuda:0")

# Optional: map 3-letter residue names to 1-letter codes
three_to_one = {
    'ALA': 'A', 'ARG': 'R', 'ASN': 'N', 'ASP': 'D',
    'CYS': 'C', 'GLN': 'Q', 'GLU': 'E', 'GLY': 'G',
    'HIS': 'H', 'ILE': 'I', 'LEU': 'L', 'LYS': 'K',
    'MET': 'M', 'PHE': 'F', 'PRO': 'P', 'SER': 'S',
    'THR': 'T', 'TRP': 'W', 'TYR': 'Y', 'VAL': 'V',
    'SEC': 'U', 'PYL': 'O', 'ASX': 'B', 'GLX': 'Z',
    'XLE': 'J', 'UNK': 'X'
}

def get_backbone_coords_from_local_pdb(pdb_path, chain_id='A', sequence_length=None, target="data", device=device):
    """
    Load backbone coordinates and residue types from a local PDB file.

    Returns:
        coords_tensor: torch.Tensor of shape (1, N, 3, 3)
        residue_types: List of one-letter residue codes
    """
    parser = PDBParser(QUIET=True)
    structure = parser.get_structure("local_structure", pdb_path)

    coords = []
    residue_types = []
    model = structure[0]

    if chain_id not in model:
        raise ValueError(f"Chain {chain_id} not found in {pdb_path}")

    chain = model[chain_id]

    for residue in chain:
        if sequence_length is not None and len(coords) >= sequence_length:
            break
        if not is_aa(residue):
            continue
        try:
            n = residue['N'].get_coord()
            ca = residue['CA'].get_coord()
            c = residue['C'].get_coord()
            coords.append([n, ca, c])
            resname = residue.get_resname().upper()
            residue_types.append(three_to_one.get(resname, 'X'))  # default to 'X' if unknown
        except KeyError:
            continue

    if not coords:
        raise ValueError("No residues with complete backbone atoms found.")

    # Add infinity-padding before and after
    pad = [[float('inf')]*3, [float('inf')]*3, [float('inf')]*3]
    coords.insert(0, pad)
    coords.append(pad)

    if target == "ParD2":
        coords = [pad, pad] + coords + [pad, pad]
    elif target == "ParD3":
        coords = [pad]*2 + coords + [pad]*6
    elif target == "TrpB4":
        coords = [pad] + coords

    coords_tensor = torch.tensor(coords, device=device).unsqueeze(0)  # (1, N, 3, 3)

    return coords_tensor, residue_types

sequence_tokenizer = EsmSequenceTokenizer()

import argparse

# set up parser
parser = parser = argparse.ArgumentParser(description="Calculating the log-likelihood of a sequence")
parser.add_argument('--target', type=str, required=True, help='Dataset as a string')
parser.add_argument('--num_samples', type=int, required=False, default=384, help='Number of samples to process (default: 100000)')
parser.add_argument('--version_number', type=str, required=False, default=1, help='Version number as a string')
parser.add_argument('--replicate', type=int, required=False, default=1, help='Replicate number as an integer')
args = parser.parse_args()

target = args.target
num_samples = args.num_samples
replicate = args.replicate

cfg_filename = "./config.yaml"
network_filename = "/global/cfs/cdirs/m4235/sebastian/models/esm3clm/esm3_clm.pt"
save_folder_name = f"{target}/base_model_{num_samples}"

cfg = OmegaConf.load(cfg_filename)
sampling_temperature=1
OmegaConf.update(cfg, "train.lightning_model_args.sampling_temperature", sampling_temperature)
esm_model = BidirectionalModel(cfg["nn"]["model"], 
                                cfg["nn"]["model_args"],
                                **cfg["train"]["lightning_model_args"]).to(device)
esm_model.load_model_from_ckpt(network_filename)
esm_model.eval()
print("")
mask_token_sequence = cfg["nn"]["model_args"]["residue_token_info"]["mask"]
bos_token_sequence = cfg["nn"]["model_args"]["residue_token_info"]["bos"]
eos_token_sequence = cfg["nn"]["model_args"]["residue_token_info"]["eos"]
pad_token_sequence = cfg["nn"]["model_args"]["residue_token_info"]["pad"]


os.makedirs(save_folder_name, exist_ok=True)

data = target #  "GB1", "ParD2", "TEV", "TrpB3F", "TrpB3I", "TrpB4"
data_root_path = "/global/cfs/projectdirs/m4235/sebastian/data"

sequence_tokenizer = EsmSequenceTokenizer()

if data.startswith("TrpB"):
    df = pd.read_csv(f"{data_root_path}/TrpB/scale2max/{data}.csv")
    with open(f"{data_root_path}/TrpB/TrpB.fasta", "r") as file:
        parent_sequence_decoded = file.readlines()[1].strip()
    
elif data == "DHFR":
    df = pd.read_csv(f"{data_root_path}/{data}/scale2max/{data}.csv")
    with open(f"{data_root_path}/{data}/{data}.fasta", "r") as file:
        nucleotide_seq = file.readlines()[1].strip()
    nucleotide_seq = Seq(nucleotide_seq)
    parent_sequence_decoded = str(nucleotide_seq.translate())  # Translate to amino acid sequence
    
else:
    df = pd.read_csv(f"{data_root_path}/{data}/scale2max/{data}.csv")
    with open(f"{data_root_path}/{data}/{data}.fasta", "r") as file:
        parent_sequence_decoded = file.readlines()[1].strip()
        
if data != "GB1":        
    muts = df["muts"].iloc[0]
else:
    muts = df["muts"].iloc[100000]

numbers = re.findall(r'\d+', muts)
mask_indices = list(map(int, numbers))
num_masks_per_sequence = num_samples // 4
num_to_generate_per_mask = 4


parent_sequence = torch.tensor(sequence_tokenizer.encode(parent_sequence_decoded, 
                                                            add_special_tokens=True), device=device).unsqueeze(0).long()
sequence_length = parent_sequence.shape[1]


all_masked_sequences = []
all_unmasked_sequences_decoded = []
all_unmasked_sequences = []
all_logps = []


while len(all_unmasked_sequences_decoded) < num_samples:
    
    print(len(all_unmasked_sequences_decoded))

    masked_sequences = parent_sequence.clone().repeat(num_to_generate_per_mask, 1)
    masked_sequences[:, mask_indices] = mask_token_sequence




    
    sequence_id = torch.ones((num_to_generate_per_mask, sequence_length), device=device).long() * 1
    
    structure_tokens = torch.ones((num_to_generate_per_mask, sequence_length), device=device).long() * 4096
    structure_tokens[:, 0] = 4098
    structure_tokens[:, -1] = 4097

    coords, residue_types = get_backbone_coords_from_local_pdb(f"{data_root_path}/{data}/{data}.pdb", chain_id='A', sequence_length=sequence_length-2, target=data) if not data.startswith("TrpB") else get_backbone_coords_from_local_pdb(f"{data_root_path}/TrpB/TrpB.pdb", chain_id='A', sequence_length=sequence_length-2, target=data)

    # parent sequence sanity check
    coords_trimmed = coords[:, 1:-1]  # shape: (1, N-2, 3, 3)

    # Step 2: Determine mask of non-padding residues (i.e., not all coords are inf)
    valid_mask = ~(torch.isinf(coords_trimmed).view(-1, 9).any(dim=1))  # shape: (N-2,)
    residues_to_compare = [r for r, valid in zip(list(parent_sequence_decoded), valid_mask) if valid]

    if residue_types != residues_to_compare:
        print("Residue mismatch detected!")
        for i, (ref, pdb) in enumerate(zip(residues_to_compare, residue_types)):
            if ref != pdb:
                print(f"Position {i}: expected {ref}, got {pdb}")
    else:
        print("Residues match.")
        print(coords.shape)

    assert coords.shape[1] == sequence_length, f"Coords length {coords.shape[1]} does not match sequence length {sequence_length}"

    # Repeat the coords tensor to match the batch size (num_to_generate_per_mask)
    coords = coords.repeat(num_to_generate_per_mask, 1, 1, 1)  # Shape becomes (num_to_generate_per_mask, sequence_length, 3, 3)

    average_plddt = torch.ones((num_to_generate_per_mask), device=device)

    per_res_plddt = torch.zeros((num_to_generate_per_mask, sequence_length), device=device)
    ss8_tokens = torch.zeros((num_to_generate_per_mask, sequence_length), device=device).long()
    sasa_tokens = torch.zeros((num_to_generate_per_mask, sequence_length), device=device).long()

    function_tokens = torch.zeros((num_to_generate_per_mask, sequence_length, 8), device=device).long()
    residue_annotation_tokens = torch.zeros((num_to_generate_per_mask, sequence_length, 16), device=device).long()




    with torch.no_grad():
        unmasked_sequences = sample_components_from_bidirectional_transformer(transformer_model=esm_model,
                                                                                masked_sequence_tokens=masked_sequences,
                                                                                structure_tokens=structure_tokens,
                                                                                average_plddt=average_plddt,
                                                                                per_res_plddt=per_res_plddt,
                                                                                ss8_tokens=ss8_tokens,
                                                                                sasa_tokens=sasa_tokens,
                                                                                function_tokens=function_tokens,
                                                                                residue_annotation_tokens=residue_annotation_tokens,
                                                                                bb_coords=coords,
                                                                                sequence_id=sequence_id,
                                                                                mask_token_sequence=mask_token_sequence,
                                                                                bos_token_sequence=bos_token_sequence,
                                                                                eos_token_sequence=eos_token_sequence,
                                                                                pad_token_sequence=pad_token_sequence,
                                                                                inference_batch_size=1)


        
        masked_indices = (masked_sequences == mask_token_sequence).float()
        logits = esm_model.nn(sequence_tokens=masked_sequences,
                                structure_tokens=structure_tokens,
                                average_plddt=average_plddt,
                                per_res_plddt=per_res_plddt,
                                ss8_tokens=ss8_tokens,
                                sasa_tokens=sasa_tokens,
                                function_tokens=function_tokens,
                                residue_annotation_tokens=residue_annotation_tokens,
                                sequence_id=sequence_id,
                                bb_coords=coords)["sequence_logits"].detach()
        logps = torch.nn.functional.log_softmax(logits/sampling_temperature, dim=-1)
        logps = torch.gather(logps, dim=-1, index=unmasked_sequences.unsqueeze(-1)).squeeze(-1)
        logps = (logps * masked_indices).sum(-1).detach()
        
        decoded_seqs = [sequence.replace(" ", "") for sequence in sequence_tokenizer.batch_decode(unmasked_sequences[:, 1:-1])]
        for seq, logp, masked_seq, unmasked_seq in zip(decoded_seqs, logps, masked_sequences, unmasked_sequences):
            if seq in all_unmasked_sequences_decoded:
                continue
            else:
                all_unmasked_sequences_decoded.append(seq)
                all_logps.append(logp)
                all_masked_sequences.append(masked_seq)
                all_unmasked_sequences.append(unmasked_seq)



all_unmasked_sequences_decoded = all_unmasked_sequences_decoded[:num_samples]
all_masked_sequences = all_masked_sequences[:num_samples]
all_unmasked_sequences = all_unmasked_sequences[:num_samples]
all_logps = all_logps[:num_samples]
    
all_masked_sequences = torch.stack(all_masked_sequences, dim=0)
all_unmasked_sequences = torch.stack(all_unmasked_sequences, dim=0)
all_logps = torch.stack(all_logps, dim=0)



to_save = {"parent_sequence": parent_sequence,
            "all_masked_sequences": all_masked_sequences,
            "all_unmasked_sequences": all_unmasked_sequences,
            "all_unmasked_sequences_decoded": all_unmasked_sequences_decoded,
            "all_logps": all_logps}
torch.save(to_save, f"{save_folder_name}/trpb_{replicate}.pt")