arXiv:2508.02834cs.LGcs.AI2025-08被引 2

模仿B细胞进化,让抗体设计自动优化生成策略。

Learning from B Cell Evolution: Adaptive Multi-Expert Diffusion for Antibody Design via Online Optimization

  • 用多个专业专家模型在线迭代更新,动态调整生成策略。
  • 不同抗原类别的最佳引导策略无需预训练即可发现。
  • 适合需要精准优化的抗体药物设计,尤其对复杂界面有效。

扩散模型在抗体设计中展现出巨大潜力,但现有方法采用统一生成策略,难以适应不同抗原的特殊需求。受B细胞亲和力成熟机制启发,我们提出首个生物驱动的框架,将物理知识融入在线元学习系统。该方法使用多个专用专家(范德华力、分子识别、能量平衡、界面几何),其参数在生成过程中根据迭代反馈动态演化,模拟自然抗体的精炼过程。相比固定协议,此自适应引导可为每个靶标发现个性化优化路径。实验表明:(1) 无需预训练即可发现不同抗原类别的最优SE(3)等变引导策略,全程保持分子对称性;(2) 通过目标特异性适配显著提升热点覆盖与界面质量,实现治疗性抗体所需的多目标平衡;(3) 建立了基于在线评估的迭代精炼范式,使每个抗体-抗原体系自主学习专属优化轨迹;(4) 在小表位到大蛋白界面等多种挑战下具有良好泛化能力,支持针对单一靶标的高精度设计。

原文摘要 · Abstract (English)

Recent advances in diffusion models have shown remarkable potential for antibody design, yet existing approaches apply uniform generation strategies that cannot adapt to each antigen's unique requirements. Inspired by B cell affinity maturation, where antibodies evolve through multi-objective optimization balancing affinity, stability, and self-avoidance, we propose the first biologically-motivated framework that leverages physics-based domain knowledge within an online meta-learning system. Our method employs multiple specialized experts (van der Waals, molecular recognition, energy balance, and interface geometry) whose parameters evolve during generation based on iterative feedback, mimicking natural antibody refinement cycles. Instead of fixed protocols, this adaptive guidance discovers personalized optimization strategies for each target. Our experiments demonstrate that this approach: (1) discovers optimal SE(3)-equivariant guidance strategies for different antigen classes without pre-training, preserving molecular symmetries throughout optimization; (2) significantly enhances hotspot coverage and interface quality through target-specific adaptation, achieving balanced multi-objective optimization characteristic of therapeutic antibodies; (3) establishes a paradigm for iterative refinement where each antibody-antigen system learns its unique optimization profile through online evaluation; (4) generalizes effectively across diverse design challenges, from small epitopes to large protein interfaces, enabling precision-focused campaigns for individual targets.

抗体设计扩散模型在线学习多目标优化

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