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Large-scale chemical language representations capture molecular structure and properties

Nature Machine Intelligence volume 4, pages 1256–1264 (2022)Cite this article

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A preprint version of the article is available at arXiv.

Abstract

Models based on machine learning can enable accurate and fast molecular property predictions, which is of interest in drug discovery and material design. Various supervised machine learning models have demonstrated promising performance, but the vast chemical space and the limited availability of property labels make supervised learning challenging. Recently, unsupervised transformer-based language models pretrained on a large unlabelled corpus have produced state-of-the-art results in many downstream natural language processing tasks. Inspired by this development, we present molecular embeddings obtained by training an efficient transformer encoder model, MoLFormer, which uses rotary positional embeddings. This model employs a linear attention mechanism, coupled with highly distributed training, on SMILES sequences of 1.1 billion unlabelled molecules from the PubChem and ZINC datasets. We show that the learned molecular representation outperforms existing baselines, including supervised and self-supervised graph neural networks and language models, on several downstream tasks from ten benchmark datasets. They perform competitively on two others. Further analyses, specifically through the lens of attention, demonstrate that MoLFormer trained on chemical SMILES indeed learns the spatial relationships between atoms within a molecule. These results provide encouraging evidence that large-scale molecular language models can capture sufficient chemical and structural information to predict various distinct molecular properties, including quantum-chemical properties.

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Fig. 1: Overview of MoLFormer pipeline.
Fig. 2: Comparison of training and validation losses for absolute and rotary embeddings.
Fig. 3

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Data availability

Data for model pretraining and fine-tuning on benchmark tasks are available at https://github.com/IBM/molformer.

Code availability

Python codes for MoLFormer training and fine-tuning, and Python notebooks for MoLFormer attention visualization, as well as instances of pretrained models, are available at https://github.com/IBM/molformer. For other enquiries contact the corresponding authors.

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Acknowledgement

We thank IBM Research for supporting this work.

Author information

Authors and Affiliations

  1. IBM Research, Yorktown Heights, New York, NY, USA

    Jerret Ross, Brian Belgodere, Vijil Chenthamarakshan, Inkit Padhi, Youssef Mroueh & Payel Das

Authors
  1. Jerret Ross
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Contributions

All authors conceived the project, developed the MoLFormer framework and designed experiments. J.R., B.B., V.C. and I.P. performed model training, fine-tuning and inference experiments. I.P. and P.D. performed attention map analyses. All authors analysed the results and wrote the paper.

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Correspondence to Jerret Ross or Payel Das.

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Extended data

Extended Data Table 1 Comparison of MOLFORMER-XL with fine-tuned MOLFORMER models that are either of smaller size or pretrained on smaller datasets on BBBP, HIV, Sider, Clintox, Tox21 and BACE classification benchmarks
Full size table
Extended Data Table 2 Performance comparison of fine-tuned MOLFORMER-XL with fine-tuned MOLFORMER models are either of smaller size or pretrained on smaller datasets on QM9 (avg MAE), QM8 (avg MAE), ESOL (RMSE), FreeSolv (RMSE), and Lipophilicity (RMSE) regression benchmarks
Full size table
Extended Data Table 3 Comparison of different MOLFORMER variants on QM9 test set, in terms of average MAE and average standard MAE. Variants considered are MOLFORMER pretrained using QM9 only, PubChem only, and PubChem+ZINC dataset. The variants with and without fine-tuning on downstream task are compared, as well as models with, (✓)Rotary, and without, (×)Rotary, rotary embeddings. Our best candidate variant (for Supplementary Table 8) is chosen based on the average MAE (Mean Absolute Error) score, lower is better
Full size table
Extended Data Table 4 Correlation with structural similarity metrics on 10000 randomly selected pairs of molecules from the PubChem dataset. Reported correlations are between (1) the pairwise similarities estimated using molecular Fingerprints and those using MOLFORMER-XL (or ChemBERTa) embeddings and (2) the number of atoms in the maximum common subgraph (MCS) of two molecules and their corresponding Euclidean distance in the embedding space
Full size table

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Ross, J., Belgodere, B., Chenthamarakshan, V. et al. Large-scale chemical language representations capture molecular structure and properties. Nat Mach Intell 4, 1256–1264 (2022). https://doi.org/10.1038/s42256-022-00580-7

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