Guofeng Zhang, Rong Han, Xiaoyu Wang, Zhiyun Li, Zongbo Han, Xiaohong Liu, Guangyu Wang
Cyclic peptides are emerging as promising molecular scaffolds in drug discovery due to their high binding affinity and structural stability. However, extending generative models from linear to cyclic peptide design remains challenging, as cyclization sharply restricts the feasible design space through coupled geometric and biophysical constraints. Moreover, limited training data has led existing approaches to rely largely on zero-shot generation or post hoc filtering, resulting in low yields of feasible designs and limited control over multi-objective trade-offs. To address these limitations, we propose FAR-DPO (Feasibility-Aware and Robust Direct Preference Optimization), an architecture-agnostic framework that steers generative models toward structurally and biophysically feasible cyclic peptide designs, particularly for challenging targets. FAR-DPO integrates feasibility-aware preference construction with difficulty-aware group-robust optimization. Specifically, it constructs within-target preference pairs through feasibility-gated multi-objective dominance and adaptively reweights predefined difficulty groups according to their current preference losses. Under a fixed generation budget, FAR-DPO increases overall success rate on the CPSea benchmark from 46.9% to 57.8% on PepGLAD and from 48.0% to 49.6% on PepFlow. These gains also extend to the hardest target quartile and are accompanied by more favorable best-per-target binding scores. Together, these results demonstrate FAR-DPO's effectiveness in improving feasibility and target-wise robustness.
AI 速览：MDSKILL 将技能记忆按状态定位、动作规划与执行控制三个功能视角组织，并用动态指标筛选高质量技能，再通过在线策略自蒸馏把互补经验内化到共享策略中，以提升智能体自我进化效率。
Skill memories encode past experiences as textual prompts to improve reinforcement learning (RL) for self-evolving agents. Complementing RL, On-Policy Self-Distillation (OPSD) provides dense, fine-grained supervision to internalize knowledge from skill-guided trajectories and accelerate policy learning. However, self-generated memories often contain noisy supervision and functionally entangled, redundant, or conflicting knowledge, making direct distillation difficult. Under limited training budgets, these issues can hinder knowledge internalization and even degrade performance. To address this problem, we propose MDSKILL, a multi-view distillation approach for skill memory internalization. MDSKILL organizes skill memories into three complementary functional views (state grounding, action planning, and execution control) and selects high-quality skills using dynamic metrics to construct view-specific and integrated reasoning branches. OPSD then transfers and consolidates complementary experiential knowledge across these branches into a shared policy, enabling efficient skill internalization and continuous agent self-evolution. We evaluate MDSKILL on three agent benchmarks against RL, skill-augmented, and self-distillation baselines that do not rely on stronger external teacher models. Without additional computational overhead, MDSKILL improves upon SOTA performance by up to 7.1% and 8.1% on ALFWorld and WebShop. Extensive ablations and evolution analyses further validate its effectiveness in knowledge internalization and policy improvement. The code is available at https://anonymous.4open.science/r/MDSKILL-CF53.