用多目标引导的离散流匹配,实现生物序列的多属性协同优化。
Multi-Objective-Guided Discrete Flow Matching for Controllable Biological Sequence Design
- 基于混合排序与方向评分引导序列生成路径
- 在5个生物属性上实现高效帕累托最优设计
- 适合需要多指标平衡的蛋白与基因序列设计
设计满足多个常冲突的功能与生物物理标准的生物序列,仍是蛋白质工程的核心挑战。尽管离散流匹配模型最近在高维序列空间中展现出高效采样潜力,但现有方法仅支持单目标,或依赖连续嵌入,会扭曲离散分布。我们提出多目标引导的离散流匹配(MOG-DFM),一个通用框架,可引导任意预训练的离散流匹配生成器,实现多个标量目标间的帕累托效率权衡。每个采样步骤中,MOG-DFM 计算候选转移的混合排序-方向得分,并应用自适应超锥过滤器以确保多目标进展的一致性。我们还训练了两个无条件离散流匹配模型:PepDFM 用于多样化肽段生成,EnhancerDFM 用于功能性增强子DNA生成,作为 MOG-DFM 的基础生成模型。我们在生成兼顾五项性质的肽段结合剂(溶血性、抗污性、溶解度、半衰期、结合亲和力)以及具有特定增强子类别和DNA形状的DNA序列方面,验证了MOG-DFM的有效性。总体而言,MOG-DFM 是一种强大的多属性引导生物分子序列设计工具。
原文摘要 · Abstract (English)
Designing biological sequences that satisfy multiple, often conflicting, functional and biophysical criteria remains a central challenge in biomolecule engineering. While discrete flow matching models have recently shown promise for efficient sampling in high-dimensional sequence spaces, existing approaches address only single objectives or require continuous embeddings that can distort discrete distributions. We present Multi-Objective-Guided Discrete Flow Matching (MOG-DFM), a general framework to steer any pretrained discrete flow matching generator toward Pareto-efficient trade-offs across multiple scalar objectives. At each sampling step, MOG-DFM computes a hybrid rank-directional score for candidate transitions and applies an adaptive hypercone filter to enforce consistent multi-objective progression. We also trained two unconditional discrete flow matching models, PepDFM for diverse peptide generation and EnhancerDFM for functional enhancer DNA generation, as base generation models for MOG-DFM. We demonstrate MOG-DFM's effectiveness in generating peptide binders optimized across five properties (hemolysis, non-fouling, solubility, half-life, and binding affinity), and in designing DNA sequences with specific enhancer classes and DNA shapes. In total, MOG-DFM proves to be a powerful tool for multi-property-guided biomolecule sequence design.
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