Effective Molecular Descriptors for Chemical Accuracy at DFT Cost: Fragmentation, Error-Cancellation, and Machine Learning.

Abstract

Recent advances in theoretical thermochemistry have allowed the study of small organic and bio-organic molecules with high accuracy. However, applications to larger molecules are still impeded by the steep scaling problem of highly accurate quantum mechanical (QM) methods, forcing the use of approximate, more cost-effective methods at a greatly reduced accuracy. One of the most successful strategies to mitigate this error is the use of systematic error-cancellation schemes, in which highly accurate QM calculations can be performed on small portions of the molecule to construct corrections to an approximate method. Herein, we build on ideas from fragmentation and error-cancellation to introduce a new family of molecular descriptors for machine learning modeled after the Connectivity-Based Hierarchy (CBH) of generalized isodesmic reaction schemes. The best performing descriptor ML(CBH-2) is constructed from fragments preserving only the immediate connectivity of all heavy (non-H) atoms of a molecule along with overlapping regions of fragments in accordance with the inclusion-exclusion principle. Our proposed approach offers a simple, chemically intuitive grouping of atoms, tuned with an optimal amount of error-cancellation, and outperforms previous structure-based descriptors using a much smaller input vector length. For a wide variety of density functionals, DFT+ΔML(CBH-2) models, trained on a set of small- to medium-sized organic HCNOSCl-containing molecules, achieved an out-of-sample MAE within 0.5 kcal/mol and 2σ (95%) confidence interval of <1.5 kcal/mol compared to accurate G4 reference values at DFT cost.