用于分子性质预测的消息传递神经网络 (MPNN)

pip -q install rdkit-pypi

pip -q install pandas
pip -q install Pillow
pip -q install matplotlib
pip -q install pydot
sudo apt-get -qq install graphviz

import os

# Temporary suppress tf logs
os.environ["TF_CPP_MIN_LOG_LEVEL"] = "3"

import tensorflow as tf
from tensorflow import keras
from tensorflow.keras import layers
import numpy as np
import pandas as pd
import matplotlib.pyplot as plt
import warnings
from rdkit import Chem
from rdkit import RDLogger
from rdkit.Chem.Draw import IPythonConsole
from rdkit.Chem.Draw import MolsToGridImage

# Temporary suppress warnings and RDKit logs
warnings.filterwarnings("ignore")
RDLogger.DisableLog("rdApp.*")

np.random.seed(42)
tf.random.set_seed(42)

csv_path = keras.utils.get_file(
    "BBBP.csv", "https://deepchemdata.s3-us-west-1.amazonaws.com/datasets/BBBP.csv"
)

df = pd.read_csv(csv_path, usecols=[1, 2, 3])
df.iloc[96:104]

class Featurizer:
    def __init__(self, allowable_sets):
        self.dim = 0
        self.features_mapping = {}
        for k, s in allowable_sets.items():
            s = sorted(list(s))
            self.features_mapping[k] = dict(zip(s, range(self.dim, len(s) + self.dim)))
            self.dim += len(s)

    def encode(self, inputs):
        output = np.zeros((self.dim,))
        for name_feature, feature_mapping in self.features_mapping.items():
            feature = getattr(self, name_feature)(inputs)
            if feature not in feature_mapping:
                continue
            output[feature_mapping[feature]] = 1.0
        return output


class AtomFeaturizer(Featurizer):
    def __init__(self, allowable_sets):
        super().__init__(allowable_sets)

    def symbol(self, atom):
        return atom.GetSymbol()

    def n_valence(self, atom):
        return atom.GetTotalValence()

    def n_hydrogens(self, atom):
        return atom.GetTotalNumHs()

    def hybridization(self, atom):
        return atom.GetHybridization().name.lower()


class BondFeaturizer(Featurizer):
    def __init__(self, allowable_sets):
        super().__init__(allowable_sets)
        self.dim += 1

    def encode(self, bond):
        output = np.zeros((self.dim,))
        if bond is None:
            output[-1] = 1.0
            return output
        output = super().encode(bond)
        return output

    def bond_type(self, bond):
        return bond.GetBondType().name.lower()

    def conjugated(self, bond):
        return bond.GetIsConjugated()


atom_featurizer = AtomFeaturizer(
    allowable_sets={
        "symbol": {"B", "Br", "C", "Ca", "Cl", "F", "H", "I", "N", "Na", "O", "P", "S"},
        "n_valence": {0, 1, 2, 3, 4, 5, 6},
        "n_hydrogens": {0, 1, 2, 3, 4},
        "hybridization": {"s", "sp", "sp2", "sp3"},
    }
)

bond_featurizer = BondFeaturizer(
    allowable_sets={
        "bond_type": {"single", "double", "triple", "aromatic"},
        "conjugated": {True, False},
    }
)

def molecule_from_smiles(smiles):
    # MolFromSmiles(m, sanitize=True) should be equivalent to
    # MolFromSmiles(m, sanitize=False) -> SanitizeMol(m) -> AssignStereochemistry(m, ...)
    molecule = Chem.MolFromSmiles(smiles, sanitize=False)

    # If sanitization is unsuccessful, catch the error, and try again without
    # the sanitization step that caused the error
    flag = Chem.SanitizeMol(molecule, catchErrors=True)
    if flag != Chem.SanitizeFlags.SANITIZE_NONE:
        Chem.SanitizeMol(molecule, sanitizeOps=Chem.SanitizeFlags.SANITIZE_ALL ^ flag)

    Chem.AssignStereochemistry(molecule, cleanIt=True, force=True)
    return molecule


def graph_from_molecule(molecule):
    # Initialize graph
    atom_features = []
    bond_features = []
    pair_indices = []

    for atom in molecule.GetAtoms():
        atom_features.append(atom_featurizer.encode(atom))

        # Add self-loops
        pair_indices.append([atom.GetIdx(), atom.GetIdx()])
        bond_features.append(bond_featurizer.encode(None))

        for neighbor in atom.GetNeighbors():
            bond = molecule.GetBondBetweenAtoms(atom.GetIdx(), neighbor.GetIdx())
            pair_indices.append([atom.GetIdx(), neighbor.GetIdx()])
            bond_features.append(bond_featurizer.encode(bond))

    return np.array(atom_features), np.array(bond_features), np.array(pair_indices)


def graphs_from_smiles(smiles_list):
    # Initialize graphs
    atom_features_list = []
    bond_features_list = []
    pair_indices_list = []

    for smiles in smiles_list:
        molecule = molecule_from_smiles(smiles)
        atom_features, bond_features, pair_indices = graph_from_molecule(molecule)

        atom_features_list.append(atom_features)
        bond_features_list.append(bond_features)
        pair_indices_list.append(pair_indices)

    # Convert lists to ragged tensors for tf.data.Dataset later on
    return (
        tf.ragged.constant(atom_features_list, dtype=tf.float32),
        tf.ragged.constant(bond_features_list, dtype=tf.float32),
        tf.ragged.constant(pair_indices_list, dtype=tf.int64),
    )


# Shuffle array of indices ranging from 0 to 2049
permuted_indices = np.random.permutation(np.arange(df.shape[0]))

# Train set: 80 % of data
train_index = permuted_indices[: int(df.shape[0] * 0.8)]
x_train = graphs_from_smiles(df.iloc[train_index].smiles)
y_train = df.iloc[train_index].p_np

# Valid set: 19 % of data
valid_index = permuted_indices[int(df.shape[0] * 0.8) : int(df.shape[0] * 0.99)]
x_valid = graphs_from_smiles(df.iloc[valid_index].smiles)
y_valid = df.iloc[valid_index].p_np

# Test set: 1 % of data
test_index = permuted_indices[int(df.shape[0] * 0.99) :]
x_test = graphs_from_smiles(df.iloc[test_index].smiles)
y_test = df.iloc[test_index].p_np

print(f"Name:\t{df.name[100]}\nSMILES:\t{df.smiles[100]}\nBBBP:\t{df.p_np[100]}")
molecule = molecule_from_smiles(df.iloc[100].smiles)
print("Molecule:")
molecule

graph = graph_from_molecule(molecule)
print("Graph (including self-loops):")
print("\tatom features\t", graph[0].shape)
print("\tbond features\t", graph[1].shape)
print("\tpair indices\t", graph[2].shape)

def prepare_batch(x_batch, y_batch):
    """Merges (sub)graphs of batch into a single global (disconnected) graph
    """

    atom_features, bond_features, pair_indices = x_batch

    # Obtain number of atoms and bonds for each graph (molecule)
    num_atoms = atom_features.row_lengths()
    num_bonds = bond_features.row_lengths()

    # Obtain partition indices (molecule_indicator), which will be used to
    # gather (sub)graphs from global graph in model later on
    molecule_indices = tf.range(len(num_atoms))
    molecule_indicator = tf.repeat(molecule_indices, num_atoms)

    # Merge (sub)graphs into a global (disconnected) graph. Adding 'increment' to
    # 'pair_indices' (and merging ragged tensors) actualizes the global graph
    gather_indices = tf.repeat(molecule_indices[:-1], num_bonds[1:])
    increment = tf.cumsum(num_atoms[:-1])
    increment = tf.pad(tf.gather(increment, gather_indices), [(num_bonds[0], 0)])
    pair_indices = pair_indices.merge_dims(outer_axis=0, inner_axis=1).to_tensor()
    pair_indices = pair_indices + increment[:, tf.newaxis]
    atom_features = atom_features.merge_dims(outer_axis=0, inner_axis=1).to_tensor()
    bond_features = bond_features.merge_dims(outer_axis=0, inner_axis=1).to_tensor()

    return (atom_features, bond_features, pair_indices, molecule_indicator), y_batch


def MPNNDataset(X, y, batch_size=32, shuffle=False):
    dataset = tf.data.Dataset.from_tensor_slices((X, (y)))
    if shuffle:
        dataset = dataset.shuffle(1024)
    return dataset.batch(batch_size).map(prepare_batch, -1).prefetch(-1)

class EdgeNetwork(layers.Layer):
    def build(self, input_shape):
        self.atom_dim = input_shape[0][-1]
        self.bond_dim = input_shape[1][-1]
        self.kernel = self.add_weight(
            shape=(self.bond_dim, self.atom_dim * self.atom_dim),
            initializer="glorot_uniform",
            name="kernel",
        )
        self.bias = self.add_weight(
            shape=(self.atom_dim * self.atom_dim), initializer="zeros", name="bias",
        )
        self.built = True

    def call(self, inputs):
        atom_features, bond_features, pair_indices = inputs

        # Apply linear transformation to bond features
        bond_features = tf.matmul(bond_features, self.kernel) + self.bias

        # Reshape for neighborhood aggregation later
        bond_features = tf.reshape(bond_features, (-1, self.atom_dim, self.atom_dim))

        # Obtain atom features of neighbors
        atom_features_neighbors = tf.gather(atom_features, pair_indices[:, 1])
        atom_features_neighbors = tf.expand_dims(atom_features_neighbors, axis=-1)

        # Apply neighborhood aggregation
        transformed_features = tf.matmul(bond_features, atom_features_neighbors)
        transformed_features = tf.squeeze(transformed_features, axis=-1)
        aggregated_features = tf.math.unsorted_segment_sum(
            transformed_features,
            pair_indices[:, 0],
            num_segments=tf.shape(atom_features)[0],
        )
        return aggregated_features


class MessagePassing(layers.Layer):
    def __init__(self, units, steps=4, **kwargs):
        super().__init__(**kwargs)
        self.units = units
        self.steps = steps

    def build(self, input_shape):
        self.atom_dim = input_shape[0][-1]
        self.message_step = EdgeNetwork()
        self.pad_length = max(0, self.units - self.atom_dim)
        self.update_step = layers.GRUCell(self.atom_dim + self.pad_length)
        self.built = True

    def call(self, inputs):
        atom_features, bond_features, pair_indices = inputs

        # Pad atom features if number of desired units exceeds atom_features dim.
        # Alternatively, a dense layer could be used here.
        atom_features_updated = tf.pad(atom_features, [(0, 0), (0, self.pad_length)])

        # Perform a number of steps of message passing
        for i in range(self.steps):
            # Aggregate information from neighbors
            atom_features_aggregated = self.message_step(
                [atom_features_updated, bond_features, pair_indices]
            )

            # Update node state via a step of GRU
            atom_features_updated, _ = self.update_step(
                atom_features_aggregated, atom_features_updated
            )
        return atom_features_updated

class PartitionPadding(layers.Layer):
    def __init__(self, batch_size, **kwargs):
        super().__init__(**kwargs)
        self.batch_size = batch_size

    def call(self, inputs):

        atom_features, molecule_indicator = inputs

        # Obtain subgraphs
        atom_features_partitioned = tf.dynamic_partition(
            atom_features, molecule_indicator, self.batch_size
        )

        # Pad and stack subgraphs
        num_atoms = [tf.shape(f)[0] for f in atom_features_partitioned]
        max_num_atoms = tf.reduce_max(num_atoms)
        atom_features_stacked = tf.stack(
            [
                tf.pad(f, [(0, max_num_atoms - n), (0, 0)])
                for f, n in zip(atom_features_partitioned, num_atoms)
            ],
            axis=0,
        )

        # Remove empty subgraphs (usually for last batch in dataset)
        gather_indices = tf.where(tf.reduce_sum(atom_features_stacked, (1, 2)) != 0)
        gather_indices = tf.squeeze(gather_indices, axis=-1)
        return tf.gather(atom_features_stacked, gather_indices, axis=0)


class TransformerEncoderReadout(layers.Layer):
    def __init__(
        self, num_heads=8, embed_dim=64, dense_dim=512, batch_size=32, **kwargs
    ):
        super().__init__(**kwargs)

        self.partition_padding = PartitionPadding(batch_size)
        self.attention = layers.MultiHeadAttention(num_heads, embed_dim)
        self.dense_proj = keras.Sequential(
            [layers.Dense(dense_dim, activation="relu"), layers.Dense(embed_dim),]
        )
        self.layernorm_1 = layers.LayerNormalization()
        self.layernorm_2 = layers.LayerNormalization()
        self.average_pooling = layers.GlobalAveragePooling1D()

    def call(self, inputs):
        x = self.partition_padding(inputs)
        padding_mask = tf.reduce_any(tf.not_equal(x, 0.0), axis=-1)
        padding_mask = padding_mask[:, tf.newaxis, tf.newaxis, :]
        attention_output = self.attention(x, x, attention_mask=padding_mask)
        proj_input = self.layernorm_1(x + attention_output)
        proj_output = self.layernorm_2(proj_input + self.dense_proj(proj_input))
        return self.average_pooling(proj_output)

def MPNNModel(
    atom_dim,
    bond_dim,
    batch_size=32,
    message_units=64,
    message_steps=4,
    num_attention_heads=8,
    dense_units=512,
):

    atom_features = layers.Input((atom_dim), dtype="float32", name="atom_features")
    bond_features = layers.Input((bond_dim), dtype="float32", name="bond_features")
    pair_indices = layers.Input((2), dtype="int32", name="pair_indices")
    molecule_indicator = layers.Input((), dtype="int32", name="molecule_indicator")

    x = MessagePassing(message_units, message_steps)(
        [atom_features, bond_features, pair_indices]
    )

    x = TransformerEncoderReadout(
        num_attention_heads, message_units, dense_units, batch_size
    )([x, molecule_indicator])

    x = layers.Dense(dense_units, activation="relu")(x)
    x = layers.Dense(1, activation="sigmoid")(x)

    model = keras.Model(
        inputs=[atom_features, bond_features, pair_indices, molecule_indicator],
        outputs=[x],
    )
    return model


mpnn = MPNNModel(
    atom_dim=x_train[0][0][0].shape[0], bond_dim=x_train[1][0][0].shape[0],
)

mpnn.compile(
    loss=keras.losses.BinaryCrossentropy(),
    optimizer=keras.optimizers.Adam(learning_rate=5e-4),
    metrics=[keras.metrics.AUC(name="AUC")],
)

keras.utils.plot_model(mpnn, show_dtype=True, show_shapes=True)

train_dataset = MPNNDataset(x_train, y_train)
valid_dataset = MPNNDataset(x_valid, y_valid)
test_dataset = MPNNDataset(x_test, y_test)

history = mpnn.fit(
    train_dataset,
    validation_data=valid_dataset,
    epochs=40,
    verbose=2,
    class_weight={0: 2.0, 1: 0.5},
)

plt.figure(figsize=(10, 6))
plt.plot(history.history["AUC"], label="train AUC")
plt.plot(history.history["val_AUC"], label="valid AUC")
plt.xlabel("Epochs", fontsize=16)
plt.ylabel("AUC", fontsize=16)
plt.legend(fontsize=16)

molecules = [molecule_from_smiles(df.smiles.values[index]) for index in test_index]
y_true = [df.p_np.values[index] for index in test_index]
y_pred = tf.squeeze(mpnn.predict(test_dataset), axis=1)

legends = [f"y_true/y_pred = {y_true[i]}/{y_pred[i]:.2f}" for i in range(len(y_true))]
MolsToGridImage(molecules, molsPerRow=4, legends=legends)