import gradio as gr
import os
import copy
import os
import torch
import subprocess
import time
from argparse import ArgumentParser, Namespace, FileType
from rdkit.Chem import RemoveHs
from functools import partial
import numpy as np
import pandas as pd
from rdkit import RDLogger
from rdkit.Chem import MolFromSmiles, AddHs
from torch_geometric.loader import DataLoader
import yaml
import sys
import csv
csv.field_size_limit(sys.maxsize)
print(torch.__version__)
os.makedirs("data/esm2_output", exist_ok=True)
os.makedirs("results", exist_ok=True)
from datasets.process_mols import (
read_molecule,
generate_conformer,
write_mol_with_coords,
)
from datasets.pdbbind import PDBBind
from utils.diffusion_utils import t_to_sigma as t_to_sigma_compl, get_t_schedule
from utils.sampling import randomize_position, sampling
from utils.utils import get_model
from utils.visualise import PDBFile
from tqdm import tqdm
from datasets.esm_embedding_preparation import esm_embedding_prep
import subprocess
device = torch.device("cuda" if torch.cuda.is_available() else "cpu")
with open(f"workdir/paper_score_model/model_parameters.yml") as f:
score_model_args = Namespace(**yaml.full_load(f))
with open(f"workdir/paper_confidence_model/model_parameters.yml") as f:
confidence_args = Namespace(**yaml.full_load(f))
import shutil
t_to_sigma = partial(t_to_sigma_compl, args=score_model_args)
model = get_model(score_model_args, device, t_to_sigma=t_to_sigma, no_parallel=True)
state_dict = torch.load(
f"workdir/paper_score_model/best_ema_inference_epoch_model.pt",
map_location=torch.device("cpu"),
)
model.load_state_dict(state_dict, strict=True)
model = model.to(device)
model.eval()
confidence_model = get_model(
confidence_args,
device,
t_to_sigma=t_to_sigma,
no_parallel=True,
confidence_mode=True,
)
state_dict = torch.load(
f"workdir/paper_confidence_model/best_model_epoch75.pt",
map_location=torch.device("cpu"),
)
confidence_model.load_state_dict(state_dict, strict=True)
confidence_model = confidence_model.to(device)
confidence_model.eval()
def get_pdb(pdb_code="", filepath=""):
try:
return filepath.name
except AttributeError as e:
if pdb_code is None or pdb_code == "":
return None
else:
os.system(f"wget -qnc https://files.rcsb.org/view/{pdb_code}.pdb")
return f"{pdb_code}.pdb"
def get_ligand(smiles="", filepath=""):
if smiles is None or smiles == "":
try:
return filepath.name
except AttributeError as e:
return None
else:
return smiles
def read_mol(molpath):
with open(molpath, "r") as fp:
lines = fp.readlines()
mol = ""
for l in lines:
mol += l
return mol
def molecule(input_pdb, ligand_pdb, original_ligand):
structure = read_mol(input_pdb)
mol = read_mol(ligand_pdb)
try:
ligand = read_mol(original_ligand.name)
_, ext = os.path.splitext(original_ligand.name)
lig_str_1 = """let original_ligand = `""" + ligand + """`"""
lig_str_2 = f"""
viewer.addModel( original_ligand, "{ext[1:]}" );
viewer.getModel(2).setStyle({{stick:{{colorscheme:"greenCarbon"}}}});"""
except AttributeError as e:
ligand = None
lig_str_1 = ""
lig_str_2 = ""
x = (
"""<!DOCTYPE html>
<html>
<head>
<meta http-equiv="content-type" content="text/html; charset=UTF-8" />
<style>
body{
font-family:sans-serif
}
.mol-container {
width: 600px;
height: 600px;
position: relative;
mx-auto:0
}
.mol-container select{
background-image:None;
}
.green{
width:20px;
height:20px;
background-color:#33ff45;
display:inline-block;
}
.magenta{
width:20px;
height:20px;
background-color:magenta;
display:inline-block;
}
</style>
<script src="https://cdnjs.cloudflare.com/ajax/libs/jquery/3.6.3/jquery.min.js" integrity="sha512-STof4xm1wgkfm7heWqFJVn58Hm3EtS31XFaagaa8VMReCXAkQnJZ+jEy8PCC/iT18dFy95WcExNHFTqLyp72eQ==" crossorigin="anonymous" referrerpolicy="no-referrer"></script>
<script src="https://3Dmol.csb.pitt.edu/build/3Dmol-min.js"></script>
</head>
<body>
<button id="startanimation">Replay diffusion process</button>
<button id="togglesurface">Toggle surface representation</button>
<div>
<span class="green"></span> Uploaded ligand position
<span class="magenta"></span> Predicted ligand position
</div>
<div id="container" class="mol-container"></div>
<script>
let ligand = `"""
+ mol
+ """`
let structure = `"""
+ structure
+ """`
"""
+ lig_str_1
+ """
let viewer = null;
let surface = false;
let surf = null;
$(document).ready(function () {
let element = $("#container");
let config = { backgroundColor: "white" };
viewer = $3Dmol.createViewer(element, config);
viewer.addModel( structure, "pdb" );
viewer.setStyle({}, {cartoon: {color: "gray"}});
viewer.zoomTo();
viewer.zoom(0.7);
viewer.addModelsAsFrames(ligand, "pdb");
viewer.animate({loop: "forward",reps: 1});
viewer.getModel(1).setStyle({stick:{colorscheme:"magentaCarbon"}});
"""
+ lig_str_2
+ """
viewer.render();
})
$("#startanimation").click(function() {
viewer.animate({loop: "forward",reps: 1});
});
$("#togglesurface").click(function() {
if (surface != true) {
surf = viewer.addSurface($3Dmol.SurfaceType.VDW, { "opacity": 0.9, "color": "white" }, { model: 0 });
surface = true;
} else {
viewer.removeAllSurfaces()
surface = false;
}
});
</script>
</body></html>"""
)
return f"""<iframe style="width: 100%; height: 700px" name="result" allow="midi; geolocation; microphone; camera;
display-capture; encrypted-media;" sandbox="allow-modals allow-forms
allow-scripts allow-same-origin allow-popups
allow-top-navigation-by-user-activation allow-downloads" allowfullscreen=""
allowpaymentrequest="" frameborder="0" srcdoc='{x}'></iframe>"""
import sys
def esm(protein_path, out_file):
print("running esm")
esm_embedding_prep(out_file, protein_path)
# create args object with defaults
os.environ["HOME"] = "esm/model_weights"
subprocess.call(
f"python esm/scripts/extract.py esm2_t33_650M_UR50D {out_file} data/esm2_output --repr_layers 33 --include per_tok",
shell=True,
env=os.environ,
)
def update(inp, file, ligand_inp, ligand_file, n_it, n_samples, actual_steps, no_final_step_noise):
pdb_path = get_pdb(inp, file)
ligand_path = get_ligand(ligand_inp, ligand_file)
esm(
pdb_path,
f"data/{os.path.basename(pdb_path)}_prepared_for_esm.fasta",
)
tr_schedule = get_t_schedule(inference_steps=n_it)
rot_schedule = tr_schedule
tor_schedule = tr_schedule
print("common t schedule", tr_schedule)
(
failures,
skipped,
confidences_list,
names_list,
run_times,
min_self_distances_list,
) = (
0,
0,
[],
[],
[],
[],
)
N = n_samples # number of samples to generate
protein_path_list = [pdb_path]
ligand_descriptions = [ligand_path]
no_random = False
ode = False
no_final_step_noise = no_final_step_noise
out_dir = "results/"
test_dataset = PDBBind(
transform=None,
root="",
protein_path_list=protein_path_list,
ligand_descriptions=ligand_descriptions,
receptor_radius=score_model_args.receptor_radius,
cache_path="data/cache",
remove_hs=score_model_args.remove_hs,
max_lig_size=None,
c_alpha_max_neighbors=score_model_args.c_alpha_max_neighbors,
matching=False,
keep_original=False,
popsize=score_model_args.matching_popsize,
maxiter=score_model_args.matching_maxiter,
all_atoms=score_model_args.all_atoms,
atom_radius=score_model_args.atom_radius,
atom_max_neighbors=score_model_args.atom_max_neighbors,
esm_embeddings_path="data/esm2_output",
require_ligand=True,
num_workers=1,
keep_local_structures=False,
)
test_loader = DataLoader(dataset=test_dataset, batch_size=1, shuffle=False)
confidence_test_dataset = PDBBind(
transform=None,
root="",
protein_path_list=protein_path_list,
ligand_descriptions=ligand_descriptions,
receptor_radius=confidence_args.receptor_radius,
cache_path="data/cache",
remove_hs=confidence_args.remove_hs,
max_lig_size=None,
c_alpha_max_neighbors=confidence_args.c_alpha_max_neighbors,
matching=False,
keep_original=False,
popsize=confidence_args.matching_popsize,
maxiter=confidence_args.matching_maxiter,
all_atoms=confidence_args.all_atoms,
atom_radius=confidence_args.atom_radius,
atom_max_neighbors=confidence_args.atom_max_neighbors,
esm_embeddings_path="data/esm2_output",
require_ligand=True,
num_workers=1,
)
confidence_complex_dict = {d.name: d for d in confidence_test_dataset}
for idx, orig_complex_graph in tqdm(enumerate(test_loader)):
if (
confidence_model is not None
and not (
confidence_args.use_original_model_cache
or confidence_args.transfer_weights
)
and orig_complex_graph.name[0] not in confidence_complex_dict.keys()
):
skipped += 1
print(
f"HAPPENING | The confidence dataset did not contain {orig_complex_graph.name[0]}. We are skipping this complex."
)
continue
try:
data_list = [copy.deepcopy(orig_complex_graph) for _ in range(N)]
randomize_position(
data_list,
score_model_args.no_torsion,
no_random,
score_model_args.tr_sigma_max,
)
pdb = None
lig = orig_complex_graph.mol[0]
visualization_list = []
for graph in data_list:
pdb = PDBFile(lig)
pdb.add(lig, 0, 0)
pdb.add(
(
orig_complex_graph["ligand"].pos
+ orig_complex_graph.original_center
)
.detach()
.cpu(),
1,
0,
)
pdb.add(
(graph["ligand"].pos + graph.original_center).detach().cpu(),
part=1,
order=1,
)
visualization_list.append(pdb)
start_time = time.time()
if confidence_model is not None and not (
confidence_args.use_original_model_cache
or confidence_args.transfer_weights
):
confidence_data_list = [
copy.deepcopy(confidence_complex_dict[orig_complex_graph.name[0]])
for _ in range(N)
]
else:
confidence_data_list = None
data_list, confidence = sampling(
data_list=data_list,
model=model,
inference_steps=actual_steps,
tr_schedule=tr_schedule,
rot_schedule=rot_schedule,
tor_schedule=tor_schedule,
device=device,
t_to_sigma=t_to_sigma,
model_args=score_model_args,
no_random=no_random,
ode=ode,
visualization_list=visualization_list,
confidence_model=confidence_model,
confidence_data_list=confidence_data_list,
confidence_model_args=confidence_args,
batch_size=1,
no_final_step_noise=no_final_step_noise,
)
ligand_pos = np.asarray(
[
complex_graph["ligand"].pos.cpu().numpy()
+ orig_complex_graph.original_center.cpu().numpy()
for complex_graph in data_list
]
)
run_times.append(time.time() - start_time)
if confidence is not None and isinstance(
confidence_args.rmsd_classification_cutoff, list
):
confidence = confidence[:, 0]
if confidence is not None:
confidence = confidence.cpu().numpy()
re_order = np.argsort(confidence)[::-1]
confidence = confidence[re_order]
confidences_list.append(confidence)
ligand_pos = ligand_pos[re_order]
write_dir = (
f'{out_dir}/index{idx}_{data_list[0]["name"][0].replace("/","-")}'
)
os.makedirs(write_dir, exist_ok=True)
confidences = []
for rank, pos in enumerate(ligand_pos):
mol_pred = copy.deepcopy(lig)
if score_model_args.remove_hs:
mol_pred = RemoveHs(mol_pred)
if rank == 0:
write_mol_with_coords(
mol_pred, pos, os.path.join(write_dir, f"rank{rank+1}.sdf")
)
confidences.append(confidence[rank])
write_mol_with_coords(
mol_pred,
pos,
os.path.join(
write_dir, f"rank{rank+1}_confidence{confidence[rank]:.2f}.sdf"
),
)
self_distances = np.linalg.norm(
ligand_pos[:, :, None, :] - ligand_pos[:, None, :, :], axis=-1
)
self_distances = np.where(
np.eye(self_distances.shape[2]), np.inf, self_distances
)
min_self_distances_list.append(np.min(self_distances, axis=(1, 2)))
filenames = []
if confidence is not None:
for rank, batch_idx in enumerate(re_order):
visualization_list[batch_idx].write(
os.path.join(write_dir, f"rank{rank+1}_reverseprocess.pdb")
)
filenames.append(
os.path.join(write_dir, f"rank{rank+1}_reverseprocess.pdb")
)
else:
for rank, batch_idx in enumerate(ligand_pos):
visualization_list[batch_idx].write(
os.path.join(write_dir, f"rank{rank+1}_reverseprocess.pdb")
)
filenames.append(
os.path.join(write_dir, f"rank{rank+1}_reverseprocess.pdb")
)
names_list.append(orig_complex_graph.name[0])
except Exception as e:
print("Failed on", orig_complex_graph["name"], e)
failures += 1
return None
# zip outputs
zippath = shutil.make_archive(
os.path.join("results", os.path.basename(pdb_path)), "zip", write_dir
)
print("Zipped outputs to", zippath)
labels = [
f"rank {i+1}, confidence {confidences[i]:.2f}" for i in range(len(filenames))
]
torch.cuda.empty_cache()
return (
molecule(pdb_path, filenames[0], ligand_file),
gr.Dropdown.update(choices=labels, value=labels[0]),
filenames,
pdb_path,
zippath,
)
def updateView(out, filenames, pdb, ligand_file):
print("updating view")
i = out # int(out.replace("rank", ""))
print(i)
i = int(i.split(",")[0].replace("rank", "")) - 1
return molecule(pdb, filenames[i], ligand_file)
demo = gr.Blocks()
with demo:
gr.Markdown("# DiffDock")
gr.Markdown(
">**DiffDock: Diffusion Steps, Twists, and Turns for Molecular Docking**, Corso, Gabriele and Stärk, Hannes and Jing, Bowen and Barzilay, Regina and Jaakkola, Tommi, arXiv:2210.01776 [GitHub](https://github.com/gcorso/diffdock)"
)
gr.Markdown("")
with gr.Box():
with gr.Row():
with gr.Column():
gr.Markdown("## Protein")
inp = gr.Textbox(
placeholder="PDB Code or upload file below", label="Input structure"
)
file = gr.File(file_count="single", label="Input PDB")
with gr.Column():
gr.Markdown("## Ligand")
ligand_inp = gr.Textbox(
placeholder="Provide SMILES input or upload mol2/sdf file below",
label="SMILES string",
)
ligand_file = gr.File(file_count="single", label="Input Ligand")
n_it = gr.Slider(value=20,
minimum=10, maximum=40, label="Number of inference steps", step=1
)
actual_steps = gr.Slider(value=18,
minimum=10, maximum=40, label="Number of actual inference steps", step=1
)
n_samples = gr.Slider(value=40,
minimum=10, maximum=40, label="Number of samples", step=1
)
no_final_step_noise = gr.Checkbox(value=True,label="No final step noise"
)
btn = gr.Button("Run predictions")
gr.Markdown("## Output")
pdb = gr.Variable()
filenames = gr.Variable()
out = gr.Dropdown(interactive=True, label="Ranked samples")
mol = gr.HTML()
output_file = gr.File(file_count="single", label="Output files")
gr.Examples(
[
[
"6w70",
"examples/6w70.pdb",
"COc1ccc(cc1)n2c3c(c(n2)C(=O)N)CCN(C3=O)c4ccc(cc4)N5CCCCC5=O",
"examples/6w70_ligand.sdf",
20,
10,
18,
True
],
[
"6moa",
"examples/6moa_protein_processed.pdb",
"",
"examples/6moa_ligand.sdf",
20,
10,
18,
True
],
[
"",
"examples/6o5u_protein_processed.pdb",
"",
"examples/6o5u_ligand.sdf",
20,
10,
18,
True
],
[
"",
"examples/6o5u_protein_processed.pdb",
"[NH3+]C[C@H]1O[C@H](O[C@@H]2[C@@H]([NH3+])C[C@H]([C@@H]([C@H]2O)O[C@H]2O[C@H](CO)[C@H]([C@@H]([C@H]2O)[NH3+])O)[NH3+])[C@@H]([C@H]([C@@H]1O)O)O",
"examples/6o5u_ligand.sdf",
20,
10,
18,
True
],
[
"",
"examples/6o5u_protein_processed.pdb",
"",
"examples/6o5u_ligand.sdf",
20,
10,
18,
True
],
[
"",
"examples/6ahs_protein_processed.pdb",
"",
"examples/6ahs_ligand.sdf",
20,
10,
18,
True
],
],
[inp, file, ligand_inp, ligand_file, n_it, n_samples, actual_steps, no_final_step_noise],
[mol, out, filenames, pdb, output_file],
# fn=update,
# cache_examples=True,
)
btn.click(
fn=update,
inputs=[inp, file, ligand_inp, ligand_file, n_it, n_samples, actual_steps, no_final_step_noise],
outputs=[mol, out, filenames, pdb, output_file],
)
out.change(fn=updateView, inputs=[out, filenames, pdb, ligand_file], outputs=mol)
demo.launch()