NS-Pep: De novo Peptide Design with Non-Standard Amino Acids

• URL: http://arxiv.org/abs/2510.03326v1
• Date: Wed, 01 Oct 2025 16:04:06 GMT
• Title: NS-Pep: De novo Peptide Design with Non-Standard Amino Acids
• Authors: Tao Guo, Junbo Yin, Yu Wang, Xin Gao,
• Abstract summary: Non-standard amino acids (NSAAs) offer improved binding affinity and improved pharmacological properties.<n>Existing peptide design methods are limited to standard amino acids, leaving NSAA-aware design largely unexplored.<n>We introduce NS-Pep, a unified framework for co-designing peptide sequences and structures with NSAAs.
• Score: 15.931688895952234
• License: http://creativecommons.org/licenses/by/4.0/
• Abstract: 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.

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