PepEVOLVE: Position-Aware Dynamic Peptide Optimization via Group-Relative Advantage

• URL: http://arxiv.org/abs/2511.16912v1
• Date: Fri, 21 Nov 2025 02:51:15 GMT
• Title: PepEVOLVE: Position-Aware Dynamic Peptide Optimization via Group-Relative Advantage
• Authors: Trieu Nguyen, Hao-Wei Pang, Shasha Feng,
• Abstract summary: PepEVOLVE is a position-aware, dynamic framework that learns both where to edit and how to dynamically optimize peptides for multi-objective improvement.<n>On a therapeutically motivated Rev-binding macrocycle benchmark, PepEVOLVE outperformed PepINVENT by reaching higher mean scores.
• Score: 0.0
• License: http://creativecommons.org/licenses/by/4.0/
• Abstract: Macrocyclic peptides are an emerging modality that combines biologics-like affinity with small-molecule-like developability, but their vast combinatorial space and multi-parameter objectives make lead optimization slow and challenging. Prior generative approaches such as PepINVENT require chemists to pre-specify mutable positions for optimization, choices that are not always known a priori, and rely on static pretraining and optimization algorithms that limit the model's ability to generalize and effectively optimize peptide sequences. We introduce PepEVOLVE, a position-aware, dynamic framework that learns both where to edit and how to dynamically optimize peptides for multi-objective improvement. PepEVOLVE (i) augments pretraining with dynamic masking and CHUCKLES shifting to improve generalization, (ii) uses a context-free multi-armed bandit router that discovers high-reward residues, and (iii) couples a novel evolving optimization algorithm with group-relative advantage to stabilize reinforcement updates. During in silico evaluations, the router policy reliably learns and concentrates probability on chemically meaningful sites that influence the peptide's properties. On a therapeutically motivated Rev-binding macrocycle benchmark, PepEVOLVE outperformed PepINVENT by reaching higher mean scores (approximately 0.8 vs. 0.6), achieving best candidates with a score of 0.95 (vs. 0.87), and converging in fewer steps under the task of optimizing permeability and lipophilicity with structural constraints. Overall, PepEVOLVE offers a practical, reproducible path to peptide lead optimization when optimal edit sites are unknown, enabling more efficient exploration and improving design quality across multiple objectives.

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