Scalable Low-Energy Molecular Conformer Generation with Quantum Mechanical Accuracy

Filipp Nikitin, Dylan M. Anstine, Saee Gopal Paliwal, Olexandr Isayev

Keywords: Conformer search, Diffusion models

Abstract: Molecular geometry is crucial for biological activity and chemical reactivity; however, computational methods for generating 3D structures are limited by the vast scale of conformational space and the complexities of stereochemistry. Here we present an approach that combines an expansive dataset of molecular conformers with generative diffusion models to address this problem. We introduce ChEMBL-3D, which contains over 250 million molecular geometries for 1.8 million drug-like compounds, optimized using AIMNet2 neural network potentials to a near-quantum mechanical accuracy with implicit solvent effects included. This dataset captures complex organic molecules in various protonation states and stereochemical configurations. We then developed LoQI, a stereochemistry-aware diffusion model that learns molecular geometry distributions directly from this data. Through graph augmentation, LoQI accurately generates molecular structures with targeted stereochemistry, representing a significant advance in modeling capabilities over previous generative methods. The model outperforms traditional approaches, achieving up to tenfold improvements in energy accuracy and effective recovery of optimal conformations. Benchmark tests on complex systems, including macrocycles and flexible molecules, as well as validation with crystal structures, show LoQI can perform low energy conformer search efficiently. The model code and dataset will be available before the workshop.

Submission Track: Benchmarking in AI for Materials Design - Full Paper

Submission Category: AI-Guided Design

Institution Location: Pittsburgh, USA

AI4Mat RLSF: Yes

Submission Number: 70