All‐Atom Protein Sequence Design Based on Geometric Deep Learning
Open accessPublished version of a preprint
Abstract
Designing sequences for specific protein backbones is a key step in creating new functional proteins. Here, we introduce GeoSeqBuilder, a deep learning framework that integrates protein sequence generation with side chain conformation prediction to produce the complete all‐atom structures for designed sequences. GeoSeqBuilder uses spatial geometric features from protein backbones and explicitly includes three‐body interactions of neighboring residues. GeoSeqBuilder achieves native residue type recovery rate of 51.6 %, comparable to ProteinMPNN and other leading methods, while accurately predicting side chain conformations. We first used GeoSeqBuilder to design sequences for thioredoxin and a hallucinated three‐helical bundle protein. All the 15 tested sequences expressed as soluble monomeric proteins with high thermal stability, and the 2 high‐resolution crystal structures solved closely match the designed models. The generated protein sequences exhibit low similarity (minimum 23 %) to the original sequences, with significantly altered hydrophobic cores. We further redesigned the hydrophobic core of glutathione peroxidase 4, and 3 of the 5 designs showed improved enzyme activity. Although further testing is needed, the high experimental success rate in our testing demonstrates that GeoSeqBuilder is a powerful tool for designing novel sequences for predefined protein structures with atomic details. GeoSeqBuilder is available at https://github.com/PKUliujl/GeoSeqBuilder .
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Flagged first, then by citations
- Authors
- Liu, J., Guo, Z., You, H., Zhang, C., & Lai, L.
- Affiliations
- Peking University (CN)
- Corresponding author
- Zhang, Changsheng
- Lai, Luhua
- Venue
- Angewandte Chemie International Edition
- Publisher
- Wiley
- Published
- 2024-11-04
- Volume
- 63
- Issue
- 50
- Pages
- e202411461-e202411461
- ISSN
- 1433-7851 (ISSN-L)
- 1521-3773
- OpenAlex
- W4402650071
- Cited by
- 10
- References
- 11
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 1
- FWCI
- 1.36
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Angewandte Chemie International Edition (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Funders
- Key Technologies Research and Development Program (2022YFA1303700)
- National Natural Science Foundation of China (21977007, 22033001, 22237002, T2321001)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Machine Learning in Bioinformatics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- protein sequence design, geometric deep learning, three-body interactions, protein backbone, thioredoxin, GPX4, enzyme activity enhancement, thermal stability
- MeSH terms
- Deep Learning, Amino Acid Sequence, Models, Molecular, Protein Conformation, Proteins, Thioredoxins
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