iterative_alignment_experiment_structure/create_alignment_dataset_fourth_round.py

import torch
import re
import pandas as pd
import numpy as np
import matplotlib.pyplot as plt
import h5py
from omegaconf import OmegaConf
from esm.tokenization.sequence_tokenizer import EsmSequenceTokenizer
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

num_replicates = 10
campaign_number = 3 # change this according to the campaign we are interested in
dataset_size = 96 # change this according to the dataset size we are interested in

sequence_tokenizer = EsmSequenceTokenizer()

datasets = ["TrpB4"]
data_root_path = "/global/cfs/projectdirs/m4235/sebastian/data"

for data in datasets:
    print(data)
    for i in range(num_replicates):
        cfg_filename = f"./config.yaml"
        cfg = OmegaConf.load(cfg_filename)
        sampling_temperature=1
        OmegaConf.update(cfg, "train.lightning_model_args.sampling_temperature", sampling_temperature)
        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"]
        
        if not data.startswith("TrpB"):
            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()
                
        else:
            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()
                
        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))
        # mask_indices = [i-1 for i in mask_indices] #convert to 0-based indexing
        
        fitness_scores = []
        
        # Load from base_model_{dataset_size}
        trpb_base = torch.load(f"./{data}/base_model_{dataset_size}/trpb_post_rd_{campaign_number-1}_{i}.pt")
        all_unmasked_sequences_decoded_base = trpb_base["all_unmasked_sequences_decoded"]
        all_unmasked_sequences_base = trpb_base["all_unmasked_sequences"]
        all_masked_sequences_base = trpb_base["all_masked_sequences"]
        all_unmasked_sequences_base = all_unmasked_sequences_base.reshape(-1, all_unmasked_sequences_base.shape[-1])
        all_logps_base = trpb_base["all_logps"]
        
        for unmasked_sequence_decoded, unmasked_sequence in zip(all_unmasked_sequences_decoded_base, all_unmasked_sequences_base):
            index_residue_0 = unmasked_sequence_decoded[mask_indices[0]-1]
            index_residue_1 = unmasked_sequence_decoded[mask_indices[1]-1]
            index_residue_2 = unmasked_sequence_decoded[mask_indices[2]-1]
            try:
                index_residue_3 = unmasked_sequence_decoded[mask_indices[3]-1]
                mutations = [index_residue_0, index_residue_1, index_residue_2, index_residue_3]
                muts = ''.join(mutations)
            except:
                mutations = [index_residue_0, index_residue_1, index_residue_2]
                muts = ''.join(mutations)
            
            df_filtered = df[df["AAs"] == muts]
            
            if len(df_filtered) == 0:
                if torch.any((unmasked_sequence[1:-1] > 23) | (unmasked_sequence[1:-1] < 4)):
                    print(f"Invalid sequence {muts}")
                    fitness_score = -2
                else:
                    print(f"Invalid sequence {muts}")
                    fitness_score = -2
            else:
                fitness_score = df_filtered["fitness"].values[0]
            fitness_scores.append(fitness_score)
        
        # Load from aligned_0_{dataset_size}
        trpb_aligned = torch.load(f"./{data}/aligned_{campaign_number-3}_{dataset_size}_{i}/trpb_post_rd_{campaign_number-1}_{i}.pt")
        all_unmasked_sequences_decoded_aligned_0 = trpb_aligned["all_unmasked_sequences_decoded"]
        all_unmasked_sequences_aligned_0 = trpb_aligned["all_unmasked_sequences"]
        all_masked_sequences_aligned_0 = trpb_aligned["all_masked_sequences"]
        all_unmasked_sequences_aligned_0 = all_unmasked_sequences_aligned_0.reshape(-1, all_unmasked_sequences_aligned_0.shape[-1])
        all_logps_aligned_0 = trpb_aligned["all_logps"]
        
        for unmasked_sequence_decoded, unmasked_sequence in zip(all_unmasked_sequences_decoded_aligned_0, all_unmasked_sequences_aligned_0):
            index_residue_0 = unmasked_sequence_decoded[mask_indices[0]-1]
            index_residue_1 = unmasked_sequence_decoded[mask_indices[1]-1]
            index_residue_2 = unmasked_sequence_decoded[mask_indices[2]-1]
            try:
                index_residue_3 = unmasked_sequence_decoded[mask_indices[3]-1]
                mutations = [index_residue_0, index_residue_1, index_residue_2, index_residue_3]
                muts = ''.join(mutations)
            except:
                mutations = [index_residue_0, index_residue_1, index_residue_2]
                muts = ''.join(mutations)
            
            df_filtered = df[df["AAs"] == muts]
            
            if len(df_filtered) == 0:
                if torch.any((unmasked_sequence[1:-1] > 23) | (unmasked_sequence[1:-1] < 4)):
                    print(f"Invalid sequence {muts}")
                    fitness_score = -2
                else:
                    print(f"Invalid sequence {muts}")
                    fitness_score = -2
            else:
                fitness_score = df_filtered["fitness"].values[0]
            fitness_scores.append(fitness_score)
        
        # Load from aligned_1_{dataset_size}
        trpb_aligned_1 = torch.load(f"./{data}/aligned_{campaign_number-2}_{dataset_size}_{i}/trpb_post_rd_{campaign_number-1}_{i}.pt")
        all_unmasked_sequences_decoded_aligned_1 = trpb_aligned_1["all_unmasked_sequences_decoded"]
        all_unmasked_sequences_aligned_1 = trpb_aligned_1["all_unmasked_sequences"]
        all_masked_sequences_aligned_1 = trpb_aligned_1["all_masked_sequences"]
        all_unmasked_sequences_aligned_1 = all_unmasked_sequences_aligned_1.reshape(-1, all_unmasked_sequences_aligned_1.shape[-1])
        all_logps_aligned_1 = trpb_aligned_1["all_logps"]

        for unmasked_sequence_decoded, unmasked_sequence in zip(all_unmasked_sequences_decoded_aligned_1, all_unmasked_sequences_aligned_1):
            index_residue_0 = unmasked_sequence_decoded[mask_indices[0]-1]
            index_residue_1 = unmasked_sequence_decoded[mask_indices[1]-1]
            index_residue_2 = unmasked_sequence_decoded[mask_indices[2]-1]
            try:
                index_residue_3 = unmasked_sequence_decoded[mask_indices[3]-1]
                mutations = [index_residue_0, index_residue_1, index_residue_2, index_residue_3]
                muts = ''.join(mutations)
            except:
                mutations = [index_residue_0, index_residue_1, index_residue_2]
                muts = ''.join(mutations)

            df_filtered = df[df["AAs"] == muts]

            if len(df_filtered) == 0:
                if torch.any((unmasked_sequence[1:-1] > 23) | (unmasked_sequence[1:-1] < 4)):
                    print(f"Invalid sequence {muts}")
                    fitness_score = -2
                else:
                    print(f"Invalid sequence {muts}")
                    fitness_score = -2
            else:
                fitness_score = df_filtered["fitness"].values[0]
            fitness_scores.append(fitness_score)
            
        # Load from aligned_2_{dataset_size}
        trpb_aligned_2 = torch.load(f"./{data}/aligned_{campaign_number-1}_{dataset_size}_{i}/trpb_{i}.pt")
        all_unmasked_sequences_decoded_aligned_2 = trpb_aligned_2["all_unmasked_sequences_decoded"]
        all_unmasked_sequences_aligned_2 = trpb_aligned_2["all_unmasked_sequences"]
        all_masked_sequences_aligned_2 = trpb_aligned_2["all_masked_sequences"]
        all_unmasked_sequences_aligned_2 = all_unmasked_sequences_aligned_2.reshape(-1, all_unmasked_sequences_aligned_2.shape[-1])
        all_logps_aligned_2 = trpb_aligned_2["all_logps"]

        for unmasked_sequence_decoded, unmasked_sequence in zip(all_unmasked_sequences_decoded_aligned_2, all_unmasked_sequences_aligned_2):
            index_residue_0 = unmasked_sequence_decoded[mask_indices[0]-1]
            index_residue_1 = unmasked_sequence_decoded[mask_indices[1]-1]
            index_residue_2 = unmasked_sequence_decoded[mask_indices[2]-1]
            try:
                index_residue_3 = unmasked_sequence_decoded[mask_indices[3]-1]
                mutations = [index_residue_0, index_residue_1, index_residue_2, index_residue_3]
                muts = ''.join(mutations)
            except:
                mutations = [index_residue_0, index_residue_1, index_residue_2]
                muts = ''.join(mutations)

            df_filtered = df[df["AAs"] == muts]

            if len(df_filtered) == 0:
                if torch.any((unmasked_sequence[1:-1] > 23) | (unmasked_sequence[1:-1] < 4)):
                    print(f"Invalid sequence {muts}")
                    fitness_score = -2
                else:
                    print(f"Invalid sequence {muts}")
                    fitness_score = -2
            else:
                fitness_score = df_filtered["fitness"].values[0]
            fitness_scores.append(fitness_score)

        
        # Concatenate the sequences and logps from all models
        all_unmasked_sequences = torch.cat((all_unmasked_sequences_base, all_unmasked_sequences_aligned_0, all_unmasked_sequences_aligned_1, all_unmasked_sequences_aligned_2),dim=0)#
        all_masked_sequences = torch.cat((all_masked_sequences_base, all_masked_sequences_aligned_0, all_masked_sequences_aligned_1, all_masked_sequences_aligned_2),dim=0)#
        print(all_logps_base.shape, all_logps_aligned_0.shape, all_logps_aligned_1.shape, all_logps_aligned_2.shape)#
        all_logps = torch.cat((all_logps_base, all_logps_aligned_0, all_logps_aligned_1, all_logps_aligned_2),dim=0)#

        all_fitness_scores = fitness_scores
        
        # Check for duplicates in all_unmasked_sequences
        unique_sequences, counts = torch.unique(all_unmasked_sequences, dim=0, return_counts=True)
        num_duplicates = torch.sum(counts > 1).item()
        print(f"Number of duplicate sequences: {num_duplicates}")
        
        all_fitness_scores = np.array(all_fitness_scores)
        all_fitness_scores = np.where(all_fitness_scores > 0, -np.log(all_fitness_scores), 10)
        
        sampling_temperature = 1 # hard-coding a sampling temperature of 1 for mixed-temperature alignment

        sequence_length = all_unmasked_sequences.shape[1]

        sequence_id = torch.ones((all_unmasked_sequences.shape[0], sequence_length), device=device).long() * 1

        structure_tokens = torch.ones((1, 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}"

        average_plddt = torch.ones((1), device=device)

        per_res_plddt = torch.zeros((1, sequence_length), device=device)
        ss8_tokens = torch.zeros((1, sequence_length), device=device).long()
        sasa_tokens = torch.zeros((1, sequence_length), device=device).long()

        function_tokens = torch.zeros((1, sequence_length, 8), device=device).long()
        residue_annotation_tokens = torch.zeros((1, sequence_length, 16), device=device).long()
                
        
        with h5py.File(f"./{data}/alignment_dataset_{campaign_number}_{dataset_size}_from_ESM3_{i}.hdf5", "w") as f:
            masked_sequence_tokens = f.create_dataset("masked_sequence_tokens", data=all_masked_sequences.cpu().numpy())
            unmasked_sequence_tokens = f.create_dataset("unmasked_sequence_tokens", data=all_unmasked_sequences.cpu().numpy())
            sequence_id = f.create_dataset("sequence_id", data=sequence_id.cpu().numpy())
            structure_tokens = f.create_dataset("structural_tokens", data=structure_tokens.cpu().numpy())
            coords = f.create_dataset("bb_coords", data=coords.cpu().numpy())
            average_plddt = f.create_dataset("average_plddt", data=average_plddt.cpu().numpy())
            per_res_plddt = f.create_dataset("per_res_plddt", data=per_res_plddt.cpu().numpy())
            ss8_tokens = f.create_dataset("ss8_tokens", data=ss8_tokens.cpu().numpy())
            sasa_tokens = f.create_dataset("sasa_tokens", data=sasa_tokens.cpu().numpy())
            function_tokens = f.create_dataset("function_tokens", data=function_tokens.cpu().numpy())
            residue_annotation_tokens = f.create_dataset("residue_annotation_tokens", data=residue_annotation_tokens.cpu().numpy())

            ref_logps = f.create_dataset("ref_logps", data=all_logps.cpu().numpy())
            energies = f.create_dataset("energies", data=all_fitness_scores)


            f.attrs["num_prompts"] = 1
            f.attrs["num_examples_per_prompt"] = masked_sequence_tokens.shape[0]
            f.attrs["fixed_bb_coords"] = True
            f.attrs["fixed_average_plddt"] = True
            f.attrs["fixed_per_res_plddt"] = True
            f.attrs["fixed_ss8_tokens"] = True
            f.attrs["fixed_sasa_tokens"] = True
            f.attrs["fixed_function_tokens"] = True
            f.attrs["fixed_residue_annotation_tokens"] = True
            f.attrs["fixed_structural_tokens"] = True
            f.attrs["sampling_temperature"] = sampling_temperature