NS-Pep: De novo Peptide Design with Non-Standard Amino Acids
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arXiv
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| Auteurs principaux: | , , , |
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| Format: | Preprint |
| Publié: |
2025
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| _version_ | 1866916987772338176 |
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| author | Guo, Tao Yin, Junbo Wang, Yu Gao, Xin |
| author_facet | Guo, Tao Yin, Junbo Wang, Yu Gao, Xin |
| contents | Peptide drugs incorporating non-standard amino acids (NSAAs) offer improved binding affinity and improved pharmacological properties. However, existing peptide design methods are limited to standard amino acids, leaving NSAA-aware design largely unexplored. We introduce NS-Pep, a unified framework for co-designing peptide sequences and structures with NSAAs. The main challenge is that NSAAs are extremely underrepresented-even the most frequent one, SEP, accounts for less than 0.4% of residues-resulting in a severe long-tailed distribution. To improve generalization to rare amino acids, we propose Residue Frequency-Guided Modification (RFGM), which mitigates over-penalization through frequency-aware logit calibration, supported by both theoretical and empirical analysis. Furthermore, we identify that insufficient side-chain modeling limits geometric representation of NSAAs. To address this, we introduce Progressive Side-chain Perception (PSP) for coarse-to-fine torsion and location prediction, and Interaction-Aware Weighting (IAW) to emphasize pocket-proximal residues. Moreover, NS-Pep generalizes naturally to the peptide folding task with NSAAs, addressing a major limitation of current tools. Experiments show that NS-Pep improves sequence recovery rate and binding affinity by 6.23% and 5.12%, respectively, and outperforms AlphaFold3 by 17.76% in peptide folding success rate. |
| format | Preprint |
| id |
arxiv_https___arxiv_org_abs_2510_03326 |
| institution | arXiv |
| publishDate | 2025 |
| record_format | arxiv |
| spellingShingle | NS-Pep: De novo Peptide Design with Non-Standard Amino Acids Guo, Tao Yin, Junbo Wang, Yu Gao, Xin Biomolecules Artificial Intelligence Peptide drugs incorporating non-standard amino acids (NSAAs) offer improved binding affinity and improved pharmacological properties. However, existing peptide design methods are limited to standard amino acids, leaving NSAA-aware design largely unexplored. We introduce NS-Pep, a unified framework for co-designing peptide sequences and structures with NSAAs. The main challenge is that NSAAs are extremely underrepresented-even the most frequent one, SEP, accounts for less than 0.4% of residues-resulting in a severe long-tailed distribution. To improve generalization to rare amino acids, we propose Residue Frequency-Guided Modification (RFGM), which mitigates over-penalization through frequency-aware logit calibration, supported by both theoretical and empirical analysis. Furthermore, we identify that insufficient side-chain modeling limits geometric representation of NSAAs. To address this, we introduce Progressive Side-chain Perception (PSP) for coarse-to-fine torsion and location prediction, and Interaction-Aware Weighting (IAW) to emphasize pocket-proximal residues. Moreover, NS-Pep generalizes naturally to the peptide folding task with NSAAs, addressing a major limitation of current tools. Experiments show that NS-Pep improves sequence recovery rate and binding affinity by 6.23% and 5.12%, respectively, and outperforms AlphaFold3 by 17.76% in peptide folding success rate. |
| title | NS-Pep: De novo Peptide Design with Non-Standard Amino Acids |
| topic | Biomolecules Artificial Intelligence |
| url | https://arxiv.org/abs/2510.03326 |