Quantitative predictions of reaction properties, such as activation energy, have been limited due to a lack of available training data. Such predictions would be useful for computer-assisted reaction mechanism generation and organic synthesis planning. We develop a template-free deep learning model to predict the activation energy given reactant and product graphs and train the model on a new, diverse data set of gas-phase quantum chemistry reactions. We demonstrate that our model achieves accurate predictions and agrees with an intuitive understanding of chemical reactivity. With the continued generation of quantitative chemical reaction data and the development of methods that leverage such data, we expect many more methods for reactivity prediction to become available in the near future.

Integrating feature learning and on-the-fly feather engineering enables fast and accurate reacitvity predictions using large or small dataset.

Reaction times, activation energies, branching ratios, yields, and many other quantitative attributes are important for precise organic syntheses and generating detailed reaction mechanisms. Often, it would be useful to be able to classify proposed reactions as fast or slow. However, quantitative chemical reaction data, especially for atom-mapped reactions, are difficult to find in existing databases. Therefore, we used automated potential energy surface exploration to generate 12,000 organic reactions involving H, C, N, and O atoms calculated at the ωB97X-D3/def2-TZVP quantum chemistry level. We report the results of geometry optimizations and frequency calculations for reactants, products, and transition states of all reactions. Additionally, we extracted atom-mapped reaction SMILES, activation energies, and enthalpies of reaction. We believe that this data will accelerate progress in automated methods for organic synthesis and reaction mechanism generation—for example, by enabling the development of novel machine learning models for quantitative reaction prediction.

Quantitative estimates of reaction barriers are essential for developing kinetic mechanisms and predicting reaction outcomes. However, the lack of experimental data and the steep scaling of accurate quantum calculations often hinder the ability to obtain reliable kinetic values. Here, we train a directed message passing neural network on nearly 24,000 diverse gas-phase reactions calculated at CCSD­(T)-F12a/cc-pVDZ-F12//ωB97X-D3/def2-TZVP. Our model uses 75% fewer parameters than previous studies, an improved reaction representation, and proper data splits to accurately estimate performance on unseen reactions. Using information from only the reactant and product, our model quickly predicts barrier heights with a testing MAE of 2.6 kcal mol–1 relative to the coupled-cluster data, making it more accurate than a good density functional theory calculation. Furthermore, our results show that future modeling efforts to estimate reaction properties would significantly benefit from fine-tuning calibration using a transfer learning technique. We anticipate this model will accelerate and improve kinetic predictions for small molecule chemistry.

Predicting how a drug-like molecule binds to a specific protein target is a core problem in drug discovery. An extremely fast computational binding method would enable key applications such as fast virtual screening or drug engineering. Existing methods are computationally expensive as they rely on heavy candidate sampling coupled with scoring, ranking, and fine-tuning steps. We challenge this paradigm with EQUIBIND, an SE(3)-equivariant geometric deep learning model performing direct-shot prediction of both i) the receptor binding location (blind docking) and ii) the ligand's bound pose and orientation. EquiBind achieves significant speed-ups and better quality compared to traditional and recent baselines. Further, we show extra improvements when coupling it with existing fine-tuning techniques at the cost of increased running time. Finally, we propose a novel and fast fine-tuning model that adjusts torsion angles of a ligand's rotatable bonds based on closed-form global minima of the von Mises angular distance to a given input atomic point cloud, avoiding previous expensive differential evolution strategies for energy minimization.