Quantum mechanics (QM) fitting experiment.

Open in Google Colab: http://data.wangyq.net/esp_notesbooks/qm_fitting.ipynb

This notebook recovers the QM fitting experiment in https://arxiv.org/abs/2010.01196

image1 Table 2: Espaloma can directly fit quantum chemical energies to produce a new molecular mechanics force fields with better accuracy than traditional force fields based on atom typing or direct chemical perception. Espaloma was fit to quantum chemical potential energies for conformations generated by optimization trajectories from multiple conformers in various datasets from QCArchive.All datasets were partitioned by molecules 80:10:10 into train:validate:test sets. We report the RMSE on training and test sets, as well as the performance of legacy force fields on the test set. All statistics are computed with predicted and reference energies centered to have zero mean for each molecule to focus on errors in relative conformational energetics, rather than on errors in predicting the heats of formation of chemical species (which the MM functional form used here is incapable of). The 95% confidence intervals annotated are calculated by via bootstrapping molecules with replacement using 1000 replicates. *: Six cyclic peptides that cannot be parametrized using OpenForceField toolkit engine~:raw-latex:cite{openff-toolkit-0.10.0} and is not included.

Since Espaloma can derive a force field solely by fitting to energies (and optionally gradients), we repeat the end-to-end fitting experiment (See notebook http://data.wangyq.net/esp_notebooks/phalkethoh_mm_small.ipynb) directly using a quantum chemical (QM) datasets used to build and evaluate MM force fields. We assessed the ability of Espaloma to learn several distinct quantum chemical datasets generated by the Open Force Field Initiativeand deposited in the MolSSI QCArchive: - PhAlkEthOH is a collection of compounds containing only the elements carbon, hydrogen, and oxygen in compounds containing phenyl rings, alkanes, ketones, and alcohols. Limited in elemental and chemical diversity, this dataset is chosen as a proof-of-concept to demonstrate the capability of Espaloma to fit and generalize quantum chemical energies when training data is sufficient to exhaustively cover the breadth of chemical environments. - OpenFF Gen2 Optimization consists of druglike molecules used in the parametrization of the Open Force Field 1.2.0 (“Parsley”) small molecule force field. This set was constructed by the Open Force Field Consortium from challenging molecule structures provided by Pfizer, Bayer, and Roche, along with diverse molecules selected from eMolecules to achieve useful coverage of chemical space. - VEHICLe, or virtual exploratory heterocyclic library, is a set of heteroaromatic ring systems of interest to drug discovery. The atoms in the molecules in this dataset have interesting chemical environments in heteroarmatic rings that present a challenge to traditional atom typing schemes, which cannot easily accomodate the nuanced distinctions in chemical environments that lead to perturbations in heterocycle structure.We use this dataset to illustrate that Espaloma performs in situations challenging to traditional force fields. - PepConf contains a variety of short peptides, including capped, cyclic, and disulfide-bonded peptides.This dataset—regenerated using the Open Force Field QCSubmit tool—explores the applicability of Espaloma to biopolymers, such as proteins.

Since nonbonded terms are generally optimized to fit other condensed-phase properties, we focused here on optimizing only the valence parameters (bond, angle, and proper and improper torsion) to fit these gas-phase quantum chemical datasets, fixing the non-bonded energies using a legacy force field. Because we are learning an MM force field that is incapable of reproducing quantum chemical heats of formation reflected as an additive offset in the quantum chemical energy targets, in both training and test sets, snapshot energies for each molecule are shifted to have zero mean. All datasets are randomly shuffled and split (by molecules) into training (80%), validation (10%), and test (10%) sets.

Installation and imports

# install conda
! pip install -q condacolab
import condacolab
! mamba install --yes --strict-channel-priority --channel jaimergp/label/unsupported-cudatoolkit-shim --channel omnia --channel omnia/label/cuda100 --channel dglteam --channel numpy openmm openmmtools openmmforcefields rdkit openff-toolkit dgl-cuda10.0 qcportal
! git clone https://github.com/choderalab/espaloma.git
import torch
import sys
import espaloma as esp

Load dataset

Choose a dataset from ["gen2", "pepconf", "vehicle", "phalkethoh"].

dataset_name = "gen2"
# dataset_name = "pepconf"
# dataset_name = "vehicle"
# dataset_name = "phalkethoh"
! wget "data.wangyq.net/esp_dataset/"$dataset_name".zip"
! unzip $dataset_name".zip"
ds = esp.data.dataset.GraphDataset.load(dataset_name)
ds_tr, ds_vl, ds_te = ds.split([8, 1, 1])

Define model

Define Espaloma stage I: graph -> atom latent representation

representation = esp.nn.Sequential(
    layer=esp.nn.layers.dgl_legacy.gn("SAGEConv"), # use SAGEConv implementation in DGL
    config=[128, "relu", 128, "relu", 128, "relu"], # 3 layers, 128 units, ReLU activation

Define Espaloma stage II and III: atom latent representation -> bond, angle, and torsion representation and parameters. And compose all three Espaloma stages into an end-to-end model.

readout = esp.nn.readout.janossy.JanossyPooling(
    in_features=128, config=[128, "relu", 128, "relu", 128, "relu"],
    out_features={              # define modular MM parameters Espaloma will assign
        1: {"e": 1, "s": 1}, # atom hardness and electronegativity
        2: {"log_coefficients": 2}, # bond linear combination, enforce positive
        3: {"log_coefficients": 2}, # angle linear combination, enforce positive
        4: {"k": 6}, # torsion barrier heights (can be positive or negative)

espaloma_model = torch.nn.Sequential(
                 representation, readout, esp.nn.readout.janossy.ExpCoefficients(),
if torch.cuda.is_available():
    espaloma_model = espaloma_model.cuda()

Loss function is specified as the MSE between predicted and reference energy.

loss_fn = esp.metrics.GraphMetric(
        base_metric=torch.nn.MSELoss(), # use mean-squared error loss
        between=['u', "u_ref"],         # between predicted and QM energies
        level="g", # compare on graph level

Define optimizer

optimizer = torch.optim.Adam(espaloma_model.parameters(), 1e-4)

Train it!

for idx_epoch in range(10000):
    for g in ds_tr:
        if torch.cuda.is_available():
            g.heterograph = g.heterograph.to("cuda:0")
        g = espaloma_model(g.heterograph)
        loss = loss_fn(g)
    torch.save(espaloma_model.state_dict(), "%s.th" % idx_epoch)


inspect_metric = esp.metrics.center(torch.nn.L1Loss()) # use mean-squared error loss
loss_tr = []
loss_vl = []
with torch.no_grad():
    for idx_epoch in range(10000):
            torch.load("%s.th" % idx_epoch)

        # training set performance
        u = []
        u_ref = []
        for g in ds_tr:
            if torch.cuda.is_available():
                g.heterograph = g.heterograph.to("cuda:0")
        u = torch.cat(u, dim=0)
        u_ref = torch.cat(u_ref, dim=0)
        loss_tr.append(inspect_metric(u, u_ref))

        # validation set performance
        u = []
        u_ref = []
        for g in ds_vl:
            if torch.cuda.is_available():
                g.heterograph = g.heterograph.to("cuda:0")
        u = torch.cat(u, dim=0)
        u_ref = torch.cat(u_ref, dim=0)
        loss_vl.append(inspect_metric(u, u_ref))
import numpy as np
loss_tr = np.array(loss_tr) * 627.5
loss_vl = np.array(loss_vl) * 627.5
from matplotlib import pyplot as plt
plt.plot(loss_tr, label="train")
plt.plot(loss_vl, label="valid")