train_2.py

import torch
from torch.utils.data import DataLoader, Subset
from torch.optim import AdamW
import torch.nn.functional as F
import torch.nn as nn
from datasets import load_from_disk
import esm
import numpy as np
import math
import os
from transformers import AutoTokenizer
from torch.optim.lr_scheduler import CosineAnnealingLR
from transformers import get_linear_schedule_with_warmup
from tqdm import tqdm
from torch.cuda.amp import autocast, GradScaler
import gc
import pdb

os.environ['CUDA_VISIBLE_DEVICES'] = '0'

##################### Hyper-parameters #############################################
max_epochs = 30
batch_size = 4
lr = 1e-4
# dropout = 0.1
margin = 10
accumulation_steps = 4  # 16
num_heads = 4
checkpoint_path = '/home/tc415/muPPIt_embedding/checkpoints/improved_train_7'
device = torch.device("cuda:0" if torch.cuda.is_available() else "cpu")

print(f'''
max_epochs = 30
batch_size = 4
lr = 1e-4
# dropout = 0.1
margin = 10
accumulation_steps = 4
num_heads = 4
checkpoint_path = '/home/tc415/muPPIt_embedding/checkpoints/improved_train_7'
''')
####################################################################################

os.makedirs(checkpoint_path, exist_ok=True)

vhse8_values = {
    'A': [0.15, -1.11, -1.35, -0.92, 0.02, -0.91, 0.36, -0.48],
    'R': [-1.47, 1.45, 1.24, 1.27, 1.55, 1.47, 1.30, 0.83],
    'N': [-0.99, 0.00, 0.69, -0.37, -0.55, 0.85, 0.73, -0.80],
    'D': [-1.15, 0.67, -0.41, -0.01, -2.68, 1.31, 0.03, 0.56],
    'C': [0.18, -1.67, -0.21, 0.00, 1.20, -1.61, -0.19, -0.41],
    'Q': [-0.96, 0.12, 0.18, 0.16, 0.09, 0.42, -0.20, -0.41],
    'E': [-1.18, 0.40, 0.10, 0.36, -2.16, -0.17, 0.91, 0.36],
    'G': [-0.20, -1.53, -2.63, 2.28, -0.53, -1.18, -1.34, 1.10],
    'H': [-0.43, -0.25, 0.37, 0.19, 0.51, 1.28, 0.93, 0.65],
    'I': [1.27, 0.14, 0.30, -1.80, 0.30, -1.61, -0.16, -0.13],
    'L': [1.36, 0.07, 0.26, -0.80, 0.22, -1.37, 0.08, -0.62],
    'K': [-1.17, 0.70, 0.80, 1.64, 0.67, 1.63, 0.13, -0.01],
    'M': [1.01, -0.53, 0.43, 0.00, 0.23, 0.10, -0.86, -0.68],
    'F': [1.52, 0.61, 0.95, -0.16, 0.25, 0.28, -1.33, -0.65],
    'P': [0.22, -0.17, -0.50, -0.05, 0.01, -1.34, 0.19, 3.56],
    'S': [-0.67, -0.86, -1.07, -0.41, -0.32, 0.27, -0.64, 0.11],
    'T': [-0.34, -0.51, -0.55, -1.06, 0.01, -0.01, -0.79, 0.39],
    'W': [1.50, 2.06, 1.79, 0.75, 0.75, 0.13, -1.06, -0.85],
    'Y': [0.61, 1.60, 1.17, 0.73, 0.53, 0.25, -0.96, -0.52],
    'V': [0.76, -0.92, 0.17, -1.91, 0.22, -1.40, -0.24, -0.03],
}

aa_to_idx = {'A': 5, 'R': 10, 'N': 17, 'D': 13, 'C': 23, 'Q': 16, 'E': 9, 'G': 6, 'H': 21, 'I': 12, 'L': 4, 'K': 15, 'M': 20, 'F': 18, 'P': 14, 'S': 8, 'T': 11, 'W': 22, 'Y': 19, 'V': 7}

vhse8_tensor = torch.zeros(24, 8)
for aa, values in vhse8_values.items():
    aa_index = aa_to_idx[aa]
    vhse8_tensor[aa_index] = torch.tensor(values)
    
vhse8_tensor = vhse8_tensor.to(device)
vhse8_tensor.requires_grad = False

train_dataset = load_from_disk('/home/tc415/muPPIt_embedding/dataset/train/ppiref_skempi_2')  #16689, 16609, 17465
val_dataset = load_from_disk('/home/tc415/muPPIt_embedding/dataset/val/ppiref_skempi_2')
tokenizer = AutoTokenizer.from_pretrained("facebook/esm2_t33_650M_UR50D")

def collate_fn(batch):
    # Unpack the batch
    binders = []
    mutants = []
    wildtypes = []
    affs = []
    
    global tokenizer

    for b in batch:
        binder = torch.tensor(b['binder_input_ids']['input_ids'][1:-1])
        mutant = torch.tensor(b['mutant_input_ids']['input_ids'][1:-1])
        wildtype = torch.tensor(b['wildtype_input_ids']['input_ids'][1:-1])

        if binder.dim() == 0 or binder.numel() == 0 or mutant.dim() == 0 or mutant.numel() == 0 or wildtype.dim() == 0 or wildtype.numel() == 0:
            continue
        binders.append(binder)  # shape: 1*L1 -> L1
        mutants.append(mutant)  # shape: 1*L2 -> L2
        wildtypes.append(wildtype)  # shape: 1*L3 -> L3

        affs.append(b['aff'])

    
    # Collate the tensors using torch's pad_sequence
    try:
        binder_input_ids = torch.nn.utils.rnn.pad_sequence(binders, batch_first=True, padding_value=tokenizer.pad_token_id)

        mutant_input_ids = torch.nn.utils.rnn.pad_sequence(mutants, batch_first=True, padding_value=tokenizer.pad_token_id)

        wildtype_input_ids = torch.nn.utils.rnn.pad_sequence(wildtypes, batch_first=True, padding_value=tokenizer.pad_token_id)
    except:
        pdb.set_trace()

    affs = torch.tensor(affs)
    # Return the collated batch
    return {
        'binder_input_ids': binder_input_ids.int(),
        'mutant_input_ids': mutant_input_ids.int(),
        'wildtype_input_ids': wildtype_input_ids.int(),
        'aff': affs
    }

class muPPIt(torch.nn.Module):
    def __init__(self, d_node, num_heads, margin, lr, device):
        super(muPPIt, self).__init__()

        self.esm, self.alphabet = esm.pretrained.esm2_t33_650M_UR50D()
        for param in self.esm.parameters():
            param.requires_grad = False

        self.attention = torch.nn.MultiheadAttention(embed_dim=d_node, num_heads=num_heads)
        self.layer_norm = torch.nn.LayerNorm(d_node)

        self.map = torch.nn.Sequential(
            torch.nn.Linear(d_node, d_node // 2), 
            torch.nn.SiLU(),
            torch.nn.Linear(d_node // 2, d_node // 4),
            torch.nn.SiLU(),
            torch.nn.Linear(d_node // 4, 1)
        )

        for layer in self.map:
            if isinstance(layer, nn.Linear): 
                nn.init.kaiming_uniform_(layer.weight, a=0, mode='fan_in', nonlinearity='leaky_relu')
                if layer.bias is not None:
                    nn.init.zeros_(layer.bias)

        self.margin = margin
        self.learning_rate = lr
        self.loss_threshold = 10  # Set a threshold for identifying hard examples

        self.device = device

        # Easy and hard example tracking
        self.easy_example_indices = np.load('/home/tc415/muPPIt_embedding/dataset/ppiref_index.npy').tolist()
        self.hard_example_indices = np.load('/home/tc415/muPPIt_embedding/dataset/skempi_index.npy').tolist()

    def forward(self, binder_tokens, wt_tokens, mut_tokens):
        device = self.device

        global vhse8_tensor

        with torch.no_grad():
            binder_pad_mask = (binder_tokens != self.alphabet.padding_idx).int()
            binder_embed = self.esm(binder_tokens, repr_layers=[33], return_contacts=True)["representations"][33] * binder_pad_mask.unsqueeze(-1)
            binder_vhse8 = vhse8_tensor[binder_tokens]
            binder_embed = torch.concat([binder_embed, binder_vhse8], dim=-1)

            mut_pad_mask = (mut_tokens != self.alphabet.padding_idx).int()
            mut_embed = self.esm(mut_tokens, repr_layers=[33], return_contacts=True)["representations"][33] * mut_pad_mask.unsqueeze(-1)
            mut_vhse8 = vhse8_tensor[mut_tokens]
            mut_embed = torch.concat([mut_embed, mut_vhse8], dim=-1)
            
            wt_pad_mask = (wt_tokens != self.alphabet.padding_idx).int()
            wt_embed = self.esm(wt_tokens, repr_layers=[33], return_contacts=True)["representations"][33] * wt_pad_mask.unsqueeze(-1)
            wt_vhse8 = vhse8_tensor[wt_tokens]
            wt_embed = torch.concat([wt_embed, wt_vhse8], dim=-1)

        binder_wt = torch.concat([binder_embed, wt_embed], dim=1)
        binder_mut = torch.concat([binder_embed, mut_embed], dim=1)

        binder_wt = binder_wt.transpose(0,1)
        binder_mut = binder_mut.transpose(0,1)

        binder_wt_attn, _ = self.attention(binder_wt, binder_wt, binder_wt)
        binder_mut_attn, _ = self.attention(binder_mut, binder_mut, binder_mut)

        binder_wt_attn = binder_wt + binder_wt_attn
        binder_mut_attn = binder_mut + binder_mut_attn

        binder_wt_attn = binder_wt_attn.transpose(0, 1)
        binder_mut_attn = binder_mut_attn.transpose(0, 1)

        binder_wt_attn = self.layer_norm(binder_wt_attn)
        binder_mut_attn = self.layer_norm(binder_mut_attn)

        mapped_binder_wt = self.map(binder_wt_attn).squeeze(-1)      # B*(L1+L2)
        mapped_binder_mut = self.map(binder_mut_attn).squeeze(-1)     # B*(L1+L2)

        distance = torch.sqrt(torch.sum((mapped_binder_wt - mapped_binder_mut) ** 2, dim=-1))
        return distance

    def compute_loss(self, binder_tokens, wt_tokens, mut_tokens, aff):
        distance = self.forward(binder_tokens, wt_tokens, mut_tokens)

        # Loss computation
        upper_loss = F.relu(distance - self.margin * (aff + 1))    # let distance < aff + 1
        lower_loss = F.relu(self.margin * aff - distance)          # let distance > aff
        loss = upper_loss + lower_loss

        loss_weights = torch.ones_like(loss) 
        hard_example_mask = loss > self.loss_threshold
        loss_weights[hard_example_mask] = 2.0  # Double the weight for hard examples
        weighted_loss = loss * loss_weights

        return weighted_loss.mean(), distance

    def step(self, batch, compute_acc=False):
        binder_tokens = batch['binder_input_ids']
        mut_tokens = batch['mutant_input_ids']
        wt_tokens = batch['wildtype_input_ids']
        aff = batch['aff']

        binder_tokens = binder_tokens.to(device)
        wt_tokens = wt_tokens.to(device)
        mut_tokens = mut_tokens.to(device)
        aff = aff.to(self.device)

        loss, distance = self.compute_loss(binder_tokens, wt_tokens, mut_tokens, aff)

        if compute_acc:
            global margin
            accuracy = torch.sum(torch.logical_and(torch.ge(distance, margin * aff), torch.le(distance, self.margin *(aff + 1))))
            return loss, accuracy
        else:
            return loss


def train(model, optimizer, scheduler, cosine_scheduler, train_dataset, val_dataset, batch_size, max_epochs=10, accumulation_steps=4):
    val_loader = DataLoader(val_dataset, batch_size=batch_size, collate_fn=collate_fn, shuffle=False, num_workers=4)
    
    max_val_acc = 0
    for epoch in range(max_epochs):
        print(f"Epoch {epoch + 1}/{max_epochs}")

        if epoch < 3:
            train_subset = Subset(train_dataset, model.easy_example_indices)
        else:
            num_hard_examples = int((epoch / max_epochs) * len(model.hard_example_indices))
            selected_hard_indices = model.hard_example_indices[:num_hard_examples]
            combined_indices = model.easy_example_indices + selected_hard_indices
            train_subset = Subset(train_dataset, combined_indices)

        train_loader = DataLoader(train_subset, batch_size=batch_size, collate_fn=collate_fn, shuffle=True, num_workers=4)
        scaler = GradScaler()

        model.train()
        running_loss = 0.0
        optimizer.zero_grad()  

        for batch_idx, batch in tqdm(enumerate(train_loader), total=len(train_loader)):
            batch = {k: v.cuda(non_blocking=True) for k, v in batch.items()}    # Transfer batch to GPU

            with autocast():
                loss = model.step(batch)

            scaler.scale(loss).backward()

            if (batch_idx + 1) % accumulation_steps == 0:
                scaler.step(optimizer)
                scaler.update()
                optimizer.zero_grad()  

                if scheduler.last_epoch < warmup_steps:
                    scheduler.step()
                else:
                    cosine_scheduler.step()

            running_loss += loss.item()

        print(f"Epoch {epoch}: Training Loss = {running_loss / len(train_loader)}")

        del train_loader, running_loss
        gc.collect()
        torch.cuda.empty_cache()

        model.eval()
        val_loss = 0.0
        val_acc = 0.0
        with torch.no_grad():
            for batch in tqdm(val_loader, total=len(val_loader)):
                batch = {k: v.cuda(non_blocking=True) for k, v in batch.items()}
                val_loss_batch, val_acc_batch = model.step(batch, compute_acc=True)
                val_loss += val_loss_batch.item()
                val_acc += val_acc_batch.item()

        print(f"Epoch {epoch}: Val Loss = {val_loss / len(val_loader)}\tVal Acc = {val_acc / len(val_dataset)}")

        if val_acc > max_val_acc:
            max_val_acc = val_acc

        global checkpoint_path
        torch.save(model.state_dict(), os.path.join(checkpoint_path, f"epoch={epoch}_acc={round(val_acc / len(val_dataset), 2)}"))


model = muPPIt(d_node=1288, num_heads=num_heads, margin=margin, lr=lr, device=device).to(device)

optimizer = AdamW(model.parameters(), lr=model.learning_rate, betas=(0.9, 0.95), weight_decay=1e-5)

total_steps = len(train_dataset) // (batch_size*accumulation_steps) * max_epochs  # Assuming batch_size=32, max_epochs=10
warmup_steps = int(0.1 * total_steps)

scheduler = get_linear_schedule_with_warmup(
    optimizer,
    num_warmup_steps=warmup_steps,
    num_training_steps=total_steps
)
cosine_scheduler = CosineAnnealingLR(optimizer, T_max=total_steps - warmup_steps, eta_min=0.1*lr)

train(model, optimizer, scheduler, cosine_scheduler, train_dataset, val_dataset, batch_size=batch_size, max_epochs=max_epochs, accumulation_steps=accumulation_steps)