MolMiner: Transformer architecture for fragment-based autoregressive generation of molecular stories

Deep generative models for molecular discovery have become a very popular choice in new high-throughput screening paradigms. These models have been developed inheriting from the advances in natural language processing and computer vision, achieving ever greater results. However, generative molecular modelling has unique challenges that are often overlooked. Chemical validity, interpretability of the generation process and flexibility to variable molecular sizes are among some of the remaining challenges for generative models in computational materials design. In this work, we propose an autoregressive approach that decomposes molecular generation into a sequence of discrete and interpretable steps using molecular fragments as units, a 'molecular story'. Enforcing chemical rules in the stories guarantees the chemical validity of the generated molecules, the discrete sequential steps of a molecular story makes the process transparent improving interpretability, and the autoregressive nature of the approach allows the size of the molecule to be a decision of the model. We demonstrate the validity of the approach in a multi-target inverse design of electroactive organic compounds, focusing on the target properties of solubility, redox potential, and synthetic accessibility. Our results show that the model can effectively bias the generation distribution according to the prompted multi-target objective.

Graph Neural Network Interatomic Potential Ensembles with Calibrated Aleatoric and Epistemic Uncertainty on Energy and Forces

Inexpensive machine learning potentials are increasingly being used to speed up structural optimization and molecular dynamics simulations of materials by iteratively predicting and applying interatomic forces. In these settings, it is crucial to detect when predictions are unreliable to avoid wrong or misleading results. Here, we present a complete framework for training and recalibrating graph neural network ensemble models to produce accurate predictions of energy and forces with calibrated uncertainty estimates. The proposed method considers both epistemic and aleatoric uncertainty and the total uncertainties are recalibrated post hoc using a nonlinear scaling function to achieve good calibration on previously unseen data, without loss of predictive accuracy. The method is demonstrated and evaluated on two challenging, publicly available datasets, ANI-1x (Smith et al.) and Transition1x (Schreiner et al.), both containing diverse conformations far from equilibrium. A detailed analysis of the predictive performance and uncertainty calibration is provided. In all experiments, the proposed method achieved low prediction error and good uncertainty calibration, with predicted uncertainty correlating with expected error, on energy and forces. To the best of our knowledge, the method presented in this paper is the first to consider a complete framework for obtaining calibrated epistemic and aleatoric uncertainty predictions on both energy and forces in ML potentials.

Transition1x -- a Dataset for Building Generalizable Reactive Machine Learning Potentials

Machine Learning (ML) models have, in contrast to their usefulness in molecular dynamics studies, had limited success as surrogate potentials for reaction barrier search. It is due to the scarcity of training data in relevant transition state regions of chemical space. Currently, available datasets for training ML models on small molecular systems almost exclusively contain configurations at or near equilibrium. In this work, we present the dataset Transition1x containing 9.6 million Density Functional Theory (DFT) calculations of forces and energies of molecular configurations on and around reaction pathways at the wB97x/6-31G(d) level of theory. The data was generated by running Nudged Elastic Band (NEB) calculations with DFT on 10k reactions while saving intermediate calculations. We train state-of-the-art equivariant graph message-passing neural network models on Transition1x and cross-validate on the popular ANI1x and QM9 datasets. We show that ML models cannot learn features in transition-state regions solely by training on hitherto popular benchmark datasets. Transition1x is a new challenging benchmark that will provide an important step towards developing next-generation ML force fields that also work far away from equilibrium configurations and reactive systems.

NeuralNEB -- Neural Networks can find Reaction Paths Fast

Quantum mechanical methods like Density Functional Theory (DFT) are used with great success alongside efficient search algorithms for studying kinetics of reactive systems. However, DFT is prohibitively expensive for large scale exploration. Machine Learning (ML) models have turned out to be excellent emulators of small molecule DFT calculations and could possibly replace DFT in such tasks. For kinetics, success relies primarily on the models capability to accurately predict the Potential Energy Surface (PES) around transition-states and Minimal Energy Paths (MEPs). Previously this has not been possible due to scarcity of relevant data in the literature. In this paper we train state of the art equivariant Graph Neural Network (GNN)-based models on around 10.000 elementary reactions from the Transition1x dataset. We apply the models as potentials for the Nudged Elastic Band (NEB) algorithm and achieve a Mean Average Error (MAE) of 0.13+/-0.03 eV on barrier energies on unseen reactions. We compare the results against equivalent models trained on QM9 and ANI1x. We also compare with and outperform Density Functional based Tight Binding (DFTB) on both accuracy and computational resource. The implication is that ML models, given relevant data, are now at a level where they can be applied for downstream tasks in quantum chemistry transcending prediction of simple molecular features.

Calibrated Uncertainty for Molecular Property Prediction using Ensembles of Message Passing Neural Networks

Data-driven methods based on machine learning have the potential to accelerate analysis of atomic structures. However, machine learning models can produce overconfident predictions and it is therefore crucial to detect and handle uncertainty carefully. Here, we extend a message passing neural network designed specifically for predicting properties of molecules and materials with a calibrated probabilistic predictive distribution. The method presented in this paper differs from the previous work by considering both aleatoric and epistemic uncertainty in a unified framework, and by re-calibrating the predictive distribution on unseen data. Through computer experiments, we show that our approach results in accurate models for predicting molecular formation energies with calibrated uncertainty in and out of the training data distribution on two public molecular benchmark datasets, QM9 and PC9. The proposed method provides a general framework for training and evaluating neural network ensemble models that are able to produce accurate predictions of properties of molecules with calibrated uncertainty.