Unified modeling of 3D molecular generation via atomic interactions with PocketXMol
Open accessPublished version of a preprint
Abstract
ABSTRACT Understanding molecular interactions is essential to structural biology and drug discovery. Despite the progress of AI models in revealing and exploiting the interaction mechanisms for various applications, they are predominantly tailored to specific tasks without fully exploiting the underlying transferability across molecular data and tasks. Here, we present PocketXMol, an atom-level generative foundation model to decipher fundamental atomic interactions for general protein-pocket-interacting molecular tasks. It adopts a novel unified generative framework with an innovative task prompt mechanism and an exclusive atom-level representation, making it applicable to diverse tasks covering structure prediction and design of small molecules and peptides, without requiring fine-tuning. PocketXMol was compared to 55 baseline models across 13 typical tasks, achieving state-of-the-art performance in 11 tasks and remaining competitive in the others. We successfully utilized PocketXMol to design novel small molecules that inhibit caspase-9 with efficacy comparable to that of commercial pan-caspase inhibitors. Furthermore, we employed PocketXMol to design PD-L1-binding peptides, demonstrating a success rate substantially higher than random library screening. Three representative peptides underwent further experiments, which validated the cellular specificity and confirmed their potential for molecular probing and therapeutics. PocketXMol presents a powerful and versatile tool with promising prospects for future applications and will have a profound impact on AI-aided drug discovery.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Accurate structure prediction of biomolecular interactions with AlphaFold 3
Abramson, J., Adler, J., Dunger, J., Evans, R., Green, T., Pritzel, A., Ronneberger, O., Willmore, L., Ballard, A. J., Bambrick, J., et al. (2024) · Nature · doi:10.1038/s41586-024-07487-w · Cited by 15,861 · see citing works
Evolutionary-scale prediction of atomic level protein structure with a language model
Lin, Z., Akin, H., Rao, R., Hie, B., Zhu, Z., Lu, W., Smetanin, N., Verkuil, R., Kabeli, O., Shmueli, Y., et al. (2022) · doi:10.1101/2022.07.20.500902 · Cited by 5,523 · see citing works
Training language models to follow instructions with human feedback
Ouyang, L., Wu, J., Jiang, X., Almeida, D., Wainwright, C. L., Mishkin, P., Zhang, C., Agarwal, S., Slama, K., Ray, A., et al. (2022) · arXiv · doi:10.48550/arxiv.2203.02155 · Cited by 4,208 · see citing works
Protein complex prediction with AlphaFold-Multimer
Evans, R., O’Neill, M., Pritzel, A., Antropova, N., Senior, A., Green, T., Žídek, A., Bates, R., Blackwell, S., Yim, J., et al. (2021) · doi:10.1101/2021.10.04.463034 · Cited by 3,808 · see citing works
Diffusion Models Beat GANs on Image Synthesis
Dhariwal, P., & Nichol, A. (2021) · arXiv · doi:10.48550/arxiv.2105.05233 · Cited by 3,362 · see citing works
The FoldX web server: an online force field
Schymkowitz, J., Borg, J., Stricher, F., Nys, R., Rousseau, F., & Serrano, L. (2005) · Nucleic Acids Research · doi:10.1093/nar/gki387 · Cited by 2,759 · see citing works
Hierarchical Text-Conditional Image Generation with CLIP Latents
Ramesh, A., Dhariwal, P., Nichol, A., Chu, C., & Chen, M. (2022) · arXiv · doi:10.48550/arxiv.2204.06125 · Cited by 2,511 · see citing works
Watson, J. L., Juergens, D., Bennett, N. R., Trippe, B. L., Yim, J., Eisenach, H. E., Ahern, W., Borst, A. J., Ragotte, R. J., Milles, L. F., et al. (2022) · doi:10.1101/2022.12.09.519842 · Cited by 2,369 · see citing works
De novo design of protein structure and function with RFdiffusion
Watson, J. L., Juergens, D., Bennett, N. R., Trippe, B. L., Yim, J., Eisenach, H. E., Ahern, W., Borst, A. J., Ragotte, R. J., Milles, L. F., et al. (2023) · Nature · doi:10.1038/s41586-023-06415-8 · Cited by 2,325 · see citing works
Robust deep learning based protein sequence design using ProteinMPNN
Dauparas, J., Anishchenko, I., Bennett, N., Bai, H., Ragotte, R. J., Milles, L. F., Wicky, B. I. M., Courbet, A., de Haas, R. J., Bethel, N., et al. (2022) · doi:10.1101/2022.06.03.494563 · Cited by 2,107 · see citing works
Robust deep learning–based protein sequence design using ProteinMPNN
Dauparas, J., Anishchenko, I., Bennett, N., Bai, H., Ragotte, R. J., Milles, L. F., Wicky, B. I. M., Courbet, A., de Haas, R. J., Bethel, N., et al. (2022) · Science · doi:10.1126/science.add2187 · Cited by 2,070 · see citing works
Varadi, M., Bertoni, D., Magana, P., Paramval, U., Pidruchna, I., Radhakrishnan, M., Tsenkov, M., Nair, S., Mirdita, M., Yeo, J., et al. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkad1011 · Cited by 2,052 · see citing works
Score-Based Generative Modeling through Stochastic Differential Equations
Song, Y., Sohl-Dickstein, J., Kingma, D. P., Kumar, A., Ermon, S., & Poole, B. (2020) · arXiv · doi:10.48550/arxiv.2011.13456 · Cited by 1,953 · see citing works
DeepSeek-R1 incentivizes reasoning in LLMs through reinforcement learning
Guo, D., Yang, D., Zhang, H., Song, J., Wang, P., Zhu, Q., Xu, R., Zhang, R., Ma, S., Bi, X., et al. (2025) · Nature · doi:10.1038/s41586-025-09422-z · Cited by 1,701 · see citing works
Self-citationscGPT: Towards Building a Foundation Model for Single-Cell Multi-omics Using Generative AI
Cui, H., Wang, C., Maan, H., Pang, K., Luo, F., & Wang, B. (2023) · doi:10.1101/2023.04.30.538439 · Cited by 1,383 · see citing works
Harnessing protein folding neural networks for peptide–protein docking
Tsaban, T., Varga, J. K., Avraham, O., Ben-Aharon, Z., Khramushin, A., & Schueler-Furman, O. (2022) · Nature Communications · doi:10.1038/s41467-021-27838-9 · Cited by 1,205 · see citing works
Transfer learning enables predictions in network biology
Theodoris, C. V., Xiao, L., Chopra, A., Chaffin, M. D., Al Sayed, Z. R., Hill, M. C., Mantineo, H., Brydon, E. M., Zeng, Z., Liu, X. S., et al. (2023) · Nature · doi:10.1038/s41586-023-06139-9 · Cited by 1,193 · see citing works
A whole-slide foundation model for digital pathology from real-world data
Xu, H., Usuyama, N., Bagga, J., Zhang, S., Rao, R., Naumann, T., Wong, C., Gero, Z., González, J., Gu, Y., et al. (2024) · Nature · doi:10.1038/s41586-024-07441-w · Cited by 921 · see citing works
Self-citationAdvances in protein structure prediction and design
Kuhlman, B., & Bradley, P. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0163-x · Cited by 806 · see citing works
Large Scale Foundation Model on Single-cell Transcriptomics
Hao, M., Gong, J., Zeng, X., Liu, C., Guo, Y., Cheng, X., Wang, T., Ma, J., Song, L., & Zhang, X. (2023) · doi:10.1101/2023.05.29.542705 · Cited by 639 · see citing works
Self-citationLarge-scale foundation model on single-cell transcriptomics
Hao, M., Gong, J., Zeng, X., Liu, C., Guo, Y., Cheng, X., Wang, T., Ma, J., Zhang, X., & Song, L. (2024) · Nature Methods · doi:10.1038/s41592-024-02305-7 · Cited by 628 · see citing works
Self-citationIlluminating protein space with a programmable generative model
Ingraham, J. B., Baranov, M., Costello, Z., Barber, K. W., Wang, W., Ismail, A., Frappier, V., Lord, D. M., Ng-Thow-Hing, C., Van Vlack, E. R., et al. (2023) · Nature · doi:10.1038/s41586-023-06728-8 · Cited by 444 · see citing works
Machine learning modeling of family wide enzyme-substrate specificity screens
Goldman, S., Das, R., Yang, K. K., & Coley, C. W. (2022) · PLOS Computational Biology · doi:10.1371/journal.pcbi.1009853 · Cited by 120 · see citing works
De novo protein design by inversion of the <scp>AlphaFold</scp> structure prediction network
Goverde, C. A., Wolf, B., Khakzad, H., Rosset, S., & Correia, B. E. (2023) · Protein Science · doi:10.1002/pro.4653 · Cited by 103 · see citing works
Flagged first, then by citations
- Authors
- Peng, X., Guo, R., Guo, F., Wang, Z., Sun, J., Guan, J., Jia, Y., Xu, Y., Huang, Y., Zhang, M., Peng, J., Wang, X., Han, C., Wang, Z., & Ma, J.
- Affiliations
- Peking University (CN)
- University of Illinois Urbana-Champaign (US)
- Tsinghua University (CN)
- Fujian Medical University (CN)
- Center for Life Sciences (CN)
- Corresponding author
- Wang, Xinquan
- Wang, Zihua
- Ma, Jianzhu
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2026-04
- Volume
- 189
- Issue
- 7
- Pages
- 1904-1922.e28
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W7130380853
- Cited by
- 22
- References
- 25
- Citations by year
- 2026: 21 · 2025: 1
- FWCI
- 76.24
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- 3D molecular generation, peptide design, structure prediction
- MeSH terms
- Humans, Models, Molecular, Peptides, Protein Binding, Drug Design, Caspase 9, Small Molecule Libraries, Drug Discovery, Caspase Inhibitors, Molecular Docking Simulation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
