Written by Evan Feinberg and Bharath Ramsundar
Copyright 2016, Stanford University
This DeepChem tutorial demonstrates how to use mach.ine learning for modeling protein-ligand binding affinity
Overview:
In this tutorial, you will trace an arc from loading a raw dataset to fitting a cutting edge ML technique for predicting binding affinities. This will be accomplished by writing simple commands to access the deepchem Python API, encompassing the following broad steps:
First, let's point to a "dataset" file. This can come in the format of a CSV file or Pandas DataFrame. Regardless
of file format, it must be columnar data, where each row is a molecular system, and each column represents
a different piece of information about that system. For instance, in this example, every row reflects a
protein-ligand complex, and the following columns are present: a unique complex identifier; the SMILES string
of the ligand; the binding affinity (Ki) of the ligand to the protein in the complex; a Python list of all lines
in a PDB file for the protein alone; and a Python list of all lines in a ligand file for the ligand alone.
This should become clearer with the example. (Make sure to set DISPLAY = True)
In [1]:
%load_ext autoreload
%autoreload 2
%pdb off
# set DISPLAY = True when running tutorial
DISPLAY = False
# set PARALLELIZE to true if you want to use ipyparallel
PARALLELIZE = False
import warnings
warnings.filterwarnings('ignore')
In [2]:
import deepchem as dc
from deepchem.utils import download_url
import os
data_dir = dc.utils.get_data_dir()
dataset_file = os.path.join(data_dir, "pdbbind_core_df.csv.gz")
if not os.path.exists(dataset_file):
print('File does not exist. Downloading file...')
download_url("https://s3-us-west-1.amazonaws.com/deepchem.io/datasets/pdbbind_core_df.csv.gz")
print('File downloaded...')
raw_dataset = dc.utils.save.load_from_disk(dataset_file)
Let's see what dataset looks like:
In [3]:
print("Type of dataset is: %s" % str(type(raw_dataset)))
print(raw_dataset[:5])
print("Shape of dataset is: %s" % str(raw_dataset.shape))
One of the missions of deepchem is to form a synapse between the chemical and the algorithmic worlds: to be able to leverage the powerful and diverse array of tools available in Python to analyze molecules. This ethos applies to visual as much as quantitative examination:
In [4]:
import nglview
import tempfile
import os
import mdtraj as md
import numpy as np
import deepchem.utils.visualization
#from deepchem.utils.visualization import combine_mdtraj, visualize_complex, convert_lines_to_mdtraj
def combine_mdtraj(protein, ligand):
chain = protein.topology.add_chain()
residue = protein.topology.add_residue("LIG", chain, resSeq=1)
for atom in ligand.topology.atoms:
protein.topology.add_atom(atom.name, atom.element, residue)
protein.xyz = np.hstack([protein.xyz, ligand.xyz])
protein.topology.create_standard_bonds()
return protein
def visualize_complex(complex_mdtraj):
ligand_atoms = [a.index for a in complex_mdtraj.topology.atoms if "LIG" in str(a.residue)]
binding_pocket_atoms = md.compute_neighbors(complex_mdtraj, 0.5, ligand_atoms)[0]
binding_pocket_residues = list(set([complex_mdtraj.topology.atom(a).residue.resSeq for a in binding_pocket_atoms]))
binding_pocket_residues = [str(r) for r in binding_pocket_residues]
binding_pocket_residues = " or ".join(binding_pocket_residues)
traj = nglview.MDTrajTrajectory( complex_mdtraj ) # load file from RCSB PDB
ngltraj = nglview.NGLWidget( traj )
ngltraj.representations = [
{ "type": "cartoon", "params": {
"sele": "protein", "color": "residueindex"
} },
{ "type": "licorice", "params": {
"sele": "(not hydrogen) and (%s)" % binding_pocket_residues
} },
{ "type": "ball+stick", "params": {
"sele": "LIG"
} }
]
return ngltraj
def visualize_ligand(ligand_mdtraj):
traj = nglview.MDTrajTrajectory( ligand_mdtraj ) # load file from RCSB PDB
ngltraj = nglview.NGLWidget( traj )
ngltraj.representations = [
{ "type": "ball+stick", "params": {"sele": "all" } } ]
return ngltraj
def convert_lines_to_mdtraj(molecule_lines):
molecule_lines = molecule_lines.strip('[').strip(']').replace("'","").replace("\\n", "").split(", ")
tempdir = tempfile.mkdtemp()
molecule_file = os.path.join(tempdir, "molecule.pdb")
with open(molecule_file, "w") as f:
for line in molecule_lines:
f.write("%s\n" % line)
molecule_mdtraj = md.load(molecule_file)
return molecule_mdtraj
first_protein, first_ligand = raw_dataset.iloc[0]["protein_pdb"], raw_dataset.iloc[0]["ligand_pdb"]
protein_mdtraj = convert_lines_to_mdtraj(first_protein)
ligand_mdtraj = convert_lines_to_mdtraj(first_ligand)
complex_mdtraj = combine_mdtraj(protein_mdtraj, ligand_mdtraj)
In [5]:
ngltraj = visualize_complex(complex_mdtraj)
ngltraj
Now that we're oriented, let's use ML to do some chemistry.
So, step (2) will entail featurizing the dataset.
The available featurizations that come standard with deepchem are ECFP4 fingerprints, RDKit descriptors, NNScore-style bdescriptors, and hybrid binding pocket descriptors. Details can be found on deepchem.io.
In [6]:
grid_featurizer = dc.feat.RdkitGridFeaturizer(
voxel_width=16.0, feature_types="voxel_combined",
voxel_feature_types=["ecfp", "splif", "hbond", "pi_stack", "cation_pi", "salt_bridge"],
ecfp_power=5, splif_power=5, parallel=True, flatten=True)
compound_featurizer = dc.feat.CircularFingerprint(size=128)
Note how we separate our featurizers into those that featurize individual chemical compounds, compound_featurizers, and those that featurize molecular complexes, complex_featurizers.
Now, let's perform the actual featurization. Calling loader.featurize() will return an instance of class Dataset. Internally, loader.featurize() (a) computes the specified features on the data, (b) transforms the inputs into X and y NumPy arrays suitable for ML algorithms, and (c) constructs a Dataset() instance that has useful methods, such as an iterator, over the featurized data. This is a little complicated, so we will use MoleculeNet to featurize the PDBBind core set for us.
In [7]:
seed = 23
np.random.seed(seed)
PDBBIND_tasks, (train_dataset, valid_dataset, test_dataset), transformers = dc.molnet.load_pdbbind_grid()
Now, we conduct a train-test split. If you'd like, you can choose splittype="scaffold" instead to perform a train-test split based on Bemis-Murcko scaffolds.
We generate separate instances of the Dataset() object to hermetically seal the train dataset from the test dataset. This style lends itself easily to validation-set type hyperparameter searches, which we will illustate in a separate section of this tutorial.
The performance of many ML algorithms hinges greatly on careful data preprocessing. Deepchem comes standard with a few options for such preprocessing.
Now, we're ready to do some learning!
To fit a deepchem model, first we instantiate one of the provided (or user-written) model classes. In this case, we have a created a convenience class to wrap around any ML model available in Sci-Kit Learn that can in turn be used to interoperate with deepchem. To instantiate an SklearnModel, you will need (a) task_types, (b) model_params, another dict as illustrated below, and (c) a model_instance defining the type of model you would like to fit, in this case a RandomForestRegressor.
In [8]:
from sklearn.ensemble import RandomForestRegressor
sklearn_model = RandomForestRegressor(n_estimators=10, max_features='sqrt')
sklearn_model.random_state = seed
model = dc.models.SklearnModel(sklearn_model)
model.fit(train_dataset)
In [9]:
from deepchem.utils.evaluate import Evaluator
import pandas as pd
metric = dc.metrics.Metric(dc.metrics.r2_score)
evaluator = Evaluator(model, train_dataset, transformers)
train_r2score = evaluator.compute_model_performance([metric])
print("RF Train set R^2 %f" % (train_r2score["r2_score"]))
evaluator = Evaluator(model, valid_dataset, transformers)
valid_r2score = evaluator.compute_model_performance([metric])
print("RF Valid set R^2 %f" % (valid_r2score["r2_score"]))
In this simple example, in few yet intuitive lines of code, we traced the machine learning arc from featurizing a raw dataset to fitting and evaluating a model.
Here, we featurized only the ligand. The signal we observed in R^2 reflects the ability of circular fingerprints and random forests to learn general features that make ligands "drug-like."
In [10]:
predictions = model.predict(test_dataset)
print(predictions)
In [14]:
# TODO(rbharath): This cell visualizes the ligand with highest predicted activity. Commenting it out for now. Fix this later
#from deepchem.utils.visualization import visualize_ligand
#top_ligand = predictions.iloc[0]['ids']
#ligand1 = convert_lines_to_mdtraj(dataset.loc[dataset['complex_id']==top_ligand]['ligand_pdb'].values[0])
#if DISPLAY:
# ngltraj = visualize_ligand(ligand1)
# ngltraj
In [15]:
# TODO(rbharath): This cell visualizes the ligand with lowest predicted activity. Commenting it out for now. Fix this later
#worst_ligand = predictions.iloc[predictions.shape[0]-2]['ids']
#ligand1 = convert_lines_to_mdtraj(dataset.loc[dataset['complex_id']==worst_ligand]['ligand_pdb'].values[0])
#if DISPLAY:
# ngltraj = visualize_ligand(ligand1)
# ngltraj
The preceding simple example, in few yet intuitive lines of code, traces the machine learning arc from featurizing a raw dataset to fitting and evaluating a model.
In this next section, we illustrate deepchem's modularity, and thereby the ease with which one can explore different featurization schemes, different models, and combinations thereof, to achieve the best performance on a given dataset. We will demonstrate this by examining protein-ligand interactions.
In the previous section, we featurized only the ligand. The signal we observed in R^2 reflects the ability of grid fingerprints and random forests to learn general features that make ligands "drug-like." In this section, we demonstrate how to use hyperparameter searching to find a higher scoring ligands.
In [11]:
def rf_model_builder(model_params, model_dir):
sklearn_model = RandomForestRegressor(**model_params)
sklearn_model.random_state = seed
return dc.models.SklearnModel(sklearn_model, model_dir)
params_dict = {
"n_estimators": [10, 50, 100],
"max_features": ["auto", "sqrt", "log2", None],
}
metric = dc.metrics.Metric(dc.metrics.r2_score)
optimizer = dc.hyper.HyperparamOpt(rf_model_builder)
best_rf, best_rf_hyperparams, all_rf_results = optimizer.hyperparam_search(
params_dict, train_dataset, valid_dataset, transformers,
metric=metric)
In [12]:
%matplotlib inline
import matplotlib
import numpy as np
import matplotlib.pyplot as plt
rf_predicted_test = best_rf.predict(test_dataset)
rf_true_test = test_dataset.y
plt.scatter(rf_predicted_test, rf_true_test)
plt.xlabel('Predicted pIC50s')
plt.ylabel('True IC50')
plt.title(r'RF predicted IC50 vs. True pIC50')
plt.xlim([2, 11])
plt.ylim([2, 11])
plt.plot([2, 11], [2, 11], color='k')
plt.show()
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