app.py

import json, time, os, sys, glob

import gradio as gr

sys.path.append('/home/user/app/ProteinMPNN/vanilla_proteinmpnn')

import matplotlib.pyplot as plt
import shutil
import warnings
import numpy as np
import torch
from torch import optim
from torch.utils.data import DataLoader
from torch.utils.data.dataset import random_split, Subset
import copy
import torch.nn as nn
import torch.nn.functional as F
import random
import os.path
from protein_mpnn_utils import loss_nll, loss_smoothed, gather_edges, gather_nodes, gather_nodes_t, cat_neighbors_nodes, _scores, _S_to_seq, tied_featurize, parse_PDB
from protein_mpnn_utils import StructureDataset, StructureDatasetPDB, ProteinMPNN
import plotly.express as px
import urllib

device = torch.device("cuda:0" if (torch.cuda.is_available()) else "cpu")
model_name="v_48_020"             # ProteinMPNN model name: v_48_002, v_48_010, v_48_020, v_48_030, v_32_002, v_32_010; v_32_020, v_32_030; v_48_010=version with 48 edges 0.10A noise
backbone_noise=0.00               # Standard deviation of Gaussian noise to add to backbone atoms

path_to_model_weights='/home/user/app/ProteinMPNN/vanilla_proteinmpnn/vanilla_model_weights'          
hidden_dim = 128
num_layers = 3 
model_folder_path = path_to_model_weights
if model_folder_path[-1] != '/':
    model_folder_path = model_folder_path + '/'
checkpoint_path = model_folder_path + f'{model_name}.pt'

checkpoint = torch.load(checkpoint_path, map_location=device) 

noise_level_print = checkpoint['noise_level']

model = ProteinMPNN(num_letters=21, node_features=hidden_dim, edge_features=hidden_dim, hidden_dim=hidden_dim, num_encoder_layers=num_layers, num_decoder_layers=num_layers, augment_eps=backbone_noise, k_neighbors=checkpoint['num_edges'])
model.to(device)
model.load_state_dict(checkpoint['model_state_dict'])
model.eval()


import re

import numpy as np

def get_pdb(pdb_code="", filepath=""):
    if pdb_code is None or pdb_code == "":
        return filepath.name
    else:
        os.system(f"wget -qnc https://files.rcsb.org/view/{pdb_code}.pdb")
        return f"{pdb_code}.pdb"

def update(inp, file,designed_chain, fixed_chain, num_seqs, sampling_temp):
    pdb_path =get_pdb(pdb_code=inp, filepath=file)
    if designed_chain == "":
        designed_chain_list = []
    else:
        designed_chain_list = re.sub("[^A-Za-z]+",",", designed_chain).split(",")

    if fixed_chain == "":
        fixed_chain_list = []
    else:
        fixed_chain_list = re.sub("[^A-Za-z]+",",", fixed_chain).split(",")

    chain_list = list(set(designed_chain_list + fixed_chain_list))
    num_seq_per_target = num_seqs
    save_score=0                      # 0 for False, 1 for True; save score=-log_prob to npy files
    save_probs=0                      # 0 for False, 1 for True; save MPNN predicted probabilites per position
    score_only=0                      # 0 for False, 1 for True; score input backbone-sequence pairs
    conditional_probs_only=0          # 0 for False, 1 for True; output conditional probabilities p(s_i given the rest of the sequence and backbone)
    conditional_probs_only_backbone=0 # 0 for False, 1 for True; if true output conditional probabilities p(s_i given backbone)
        
    batch_size=1                      # Batch size; can set higher for titan, quadro GPUs, reduce this if running out of GPU memory
    max_length=20000                  # Max sequence length
        
    out_folder='.'                    # Path to a folder to output sequences, e.g. /home/out/
    jsonl_path=''                     # Path to a folder with parsed pdb into jsonl
    omit_AAs='X'                      # Specify which amino acids should be omitted in the generated sequence, e.g. 'AC' would omit alanine and cystine.
    
    pssm_multi=0.0                    # A value between [0.0, 1.0], 0.0 means do not use pssm, 1.0 ignore MPNN predictions
    pssm_threshold=0.0                # A value between -inf + inf to restric per position AAs
    pssm_log_odds_flag=0               # 0 for False, 1 for True
    pssm_bias_flag=0                   # 0 for False, 1 for True
    
    folder_for_outputs = out_folder

    NUM_BATCHES = num_seq_per_target//batch_size
    BATCH_COPIES = batch_size
    temperatures = [sampling_temp]
    omit_AAs_list = omit_AAs
    alphabet = 'ACDEFGHIKLMNPQRSTVWYX'

    omit_AAs_np = np.array([AA in omit_AAs_list for AA in alphabet]).astype(np.float32)

    chain_id_dict = None
    fixed_positions_dict = None
    pssm_dict = None
    omit_AA_dict = None
    bias_AA_dict = None
    tied_positions_dict = None
    bias_by_res_dict = None
    bias_AAs_np = np.zeros(len(alphabet))


    ###############################################################
    pdb_dict_list = parse_PDB(pdb_path, input_chain_list=chain_list)
    dataset_valid = StructureDatasetPDB(pdb_dict_list, truncate=None, max_length=max_length)

    chain_id_dict = {}
    chain_id_dict[pdb_dict_list[0]['name']]= (designed_chain_list, fixed_chain_list)
    with torch.no_grad():
        for ix, protein in enumerate(dataset_valid):
            score_list = []
            all_probs_list = []
            all_log_probs_list = []
            S_sample_list = []
            batch_clones = [copy.deepcopy(protein) for i in range(BATCH_COPIES)]
            X, S, mask, lengths, chain_M, chain_encoding_all, chain_list_list, visible_list_list, masked_list_list, masked_chain_length_list_list, chain_M_pos, omit_AA_mask, residue_idx, dihedral_mask, tied_pos_list_of_lists_list, pssm_coef, pssm_bias, pssm_log_odds_all, bias_by_res_all, tied_beta = tied_featurize(batch_clones, device, chain_id_dict, fixed_positions_dict, omit_AA_dict, tied_positions_dict, pssm_dict, bias_by_res_dict)
            pssm_log_odds_mask = (pssm_log_odds_all > pssm_threshold).float() #1.0 for true, 0.0 for false
            name_ = batch_clones[0]['name']

            randn_1 = torch.randn(chain_M.shape, device=X.device)
            log_probs = model(X, S, mask, chain_M*chain_M_pos, residue_idx, chain_encoding_all, randn_1)
            mask_for_loss = mask*chain_M*chain_M_pos
            scores = _scores(S, log_probs, mask_for_loss)
            native_score = scores.cpu().data.numpy()
            message=""
            for temp in temperatures:
                for j in range(NUM_BATCHES):
                    randn_2 = torch.randn(chain_M.shape, device=X.device)
                    if tied_positions_dict == None:
                        sample_dict = model.sample(X, randn_2, S, chain_M, chain_encoding_all, residue_idx, mask=mask, temperature=temp, omit_AAs_np=omit_AAs_np, bias_AAs_np=bias_AAs_np, chain_M_pos=chain_M_pos, omit_AA_mask=omit_AA_mask, pssm_coef=pssm_coef, pssm_bias=pssm_bias, pssm_multi=pssm_multi, pssm_log_odds_flag=bool(pssm_log_odds_flag), pssm_log_odds_mask=pssm_log_odds_mask, pssm_bias_flag=bool(pssm_bias_flag), bias_by_res=bias_by_res_all)
                        S_sample = sample_dict["S"] 
                    else:
                        sample_dict = model.tied_sample(X, randn_2, S, chain_M, chain_encoding_all, residue_idx, mask=mask, temperature=temp, omit_AAs_np=omit_AAs_np, bias_AAs_np=bias_AAs_np, chain_M_pos=chain_M_pos, omit_AA_mask=omit_AA_mask, pssm_coef=pssm_coef, pssm_bias=pssm_bias, pssm_multi=pssm_multi, pssm_log_odds_flag=bool(pssm_log_odds_flag), pssm_log_odds_mask=pssm_log_odds_mask, pssm_bias_flag=bool(pssm_bias_flag), tied_pos=tied_pos_list_of_lists_list[0], tied_beta=tied_beta, bias_by_res=bias_by_res_all)
                    # Compute scores
                        S_sample = sample_dict["S"]
                    log_probs = model(X, S_sample, mask, chain_M*chain_M_pos, residue_idx, chain_encoding_all, randn_2, use_input_decoding_order=True, decoding_order=sample_dict["decoding_order"])
                    mask_for_loss = mask*chain_M*chain_M_pos
                    scores = _scores(S_sample, log_probs, mask_for_loss)
                    scores = scores.cpu().data.numpy()
                    all_probs_list.append(sample_dict["probs"].cpu().data.numpy())
                    all_log_probs_list.append(log_probs.cpu().data.numpy())
                    S_sample_list.append(S_sample.cpu().data.numpy())
                    for b_ix in range(BATCH_COPIES):
                        masked_chain_length_list = masked_chain_length_list_list[b_ix]
                        masked_list = masked_list_list[b_ix]
                        seq_recovery_rate = torch.sum(torch.sum(torch.nn.functional.one_hot(S[b_ix], 21)*torch.nn.functional.one_hot(S_sample[b_ix], 21),axis=-1)*mask_for_loss[b_ix])/torch.sum(mask_for_loss[b_ix])
                        seq = _S_to_seq(S_sample[b_ix], chain_M[b_ix])
                        score = scores[b_ix]
                        score_list.append(score)
                        native_seq = _S_to_seq(S[b_ix], chain_M[b_ix])
                        if b_ix == 0 and j==0 and temp==temperatures[0]:
                            start = 0
                            end = 0
                            list_of_AAs = []
                            for mask_l in masked_chain_length_list:
                                end += mask_l
                                list_of_AAs.append(native_seq[start:end])
                                start = end
                            native_seq = "".join(list(np.array(list_of_AAs)[np.argsort(masked_list)]))
                            l0 = 0
                            for mc_length in list(np.array(masked_chain_length_list)[np.argsort(masked_list)])[:-1]:
                                l0 += mc_length
                                native_seq = native_seq[:l0] + '/' + native_seq[l0:]
                                l0 += 1
                            sorted_masked_chain_letters = np.argsort(masked_list_list[0])
                            print_masked_chains = [masked_list_list[0][i] for i in sorted_masked_chain_letters]
                            sorted_visible_chain_letters = np.argsort(visible_list_list[0])
                            print_visible_chains = [visible_list_list[0][i] for i in sorted_visible_chain_letters]
                            native_score_print = np.format_float_positional(np.float32(native_score.mean()), unique=False, precision=4)
                            line = '>{}, score={}, fixed_chains={}, designed_chains={}, model_name={}\n{}\n'.format(name_, native_score_print, print_visible_chains, print_masked_chains, model_name, native_seq)
                            message+=f"{line}\n"
                        start = 0
                        end = 0
                        list_of_AAs = []
                        for mask_l in masked_chain_length_list:
                            end += mask_l
                            list_of_AAs.append(seq[start:end])
                            start = end

                        seq = "".join(list(np.array(list_of_AAs)[np.argsort(masked_list)]))
                        l0 = 0
                        for mc_length in list(np.array(masked_chain_length_list)[np.argsort(masked_list)])[:-1]:
                            l0 += mc_length
                            seq = seq[:l0] + '/' + seq[l0:]
                            l0 += 1
                        score_print = np.format_float_positional(np.float32(score), unique=False, precision=4)
                        seq_rec_print = np.format_float_positional(np.float32(seq_recovery_rate.detach().cpu().numpy()), unique=False, precision=4)
                        line = '>T={}, sample={}, score={}, seq_recovery={}\n{}\n'.format(temp,b_ix,score_print,seq_rec_print,seq)
                        message+=f"{line}\n"

    all_probs_concat = np.concatenate(all_probs_list)
    all_log_probs_concat = np.concatenate(all_log_probs_list)
    S_sample_concat = np.concatenate(S_sample_list)
    fig = px.imshow(all_probs_concat.mean(0).T,
                labels=dict(x="positions", y="amino acids", color="probability"),
                y=list(alphabet), 
                template="simple_white"
               )
    fig.update_xaxes(side="top")
    return message, fig



proteinMPNN = gr.Blocks()

with proteinMPNN:
    gr.Markdown("# ProteinMPNN")
    gr.Markdown("""Citation: **Robust deep learning based protein sequence design using ProteinMPNN** <br>
Justas Dauparas, Ivan Anishchenko, Nathaniel Bennett, Hua Bai, Robert J. Ragotte, Lukas F. Milles, Basile I. M. Wicky, Alexis Courbet, Robbert J. de Haas, Neville Bethel, Philip J. Y. Leung, Timothy F. Huddy, Sam Pellock, Doug Tischer, Frederick Chan, Brian Koepnick, Hannah Nguyen, Alex Kang, Banumathi Sankaran, Asim Bera, Neil P. King, David Baker <br>
bioRxiv 2022.06.03.494563; doi: [10.1101/2022.06.03.494563](https://doi.org/10.1101/2022.06.03.494563) <br><br> Server built by [@simonduerr](https://twitter.com/simonduerr) and hosted by Huggingface""")
    with gr.Tabs():
        with gr.TabItem("Input"):
            inp = gr.Textbox( placeholder="PDB Code or upload file below", label="Input structure"
            )
            file = gr.File(file_count="single", type="file")
            
        with gr.TabItem("Settings"):
            with gr.Row():
                designed_chain = gr.Textbox(value="A", label="Designed chain")
                fixed_chain = gr.Textbox(placeholder="Use commas to fix multiple chains", label="Fixed chain")
            with gr.Row():
                num_seqs = gr.Slider(minimum=1,maximum=50, value=1,step=1, label="Number of sequences")
                sampling_temp = gr.Radio(choices=[0.1, 0.15, 0.2, 0.25, 0.3], value=0.1, label="Sampling temperature")
        btn = gr.Button("Run")
    gr.Markdown(
        """ Sampling temperature for amino acids, `T=0.0` means taking argmax, `T>>1.0` means sample randomly. Suggested values `0.1, 0.15, 0.2, 0.25, 0.3`. Higher values will lead to more diversity.
    """
    )


    gr.Markdown("# Output")
    out = gr.Textbox(label="status")
    plot = gr.Plot()
    btn.click(fn=update, inputs=[inp, file, designed_chain, fixed_chain, num_seqs, sampling_temp], outputs=[out, plot])

proteinMPNN.launch(share=True)