发表机构
University of Pennsylvania; Duke University（宾夕法尼亚大学; 杜克大学）
机构由 AI 辅助整理，请以论文原文为准。AI 中文总结
pCoMole提出基于离散流匹配的帕累托约束分子编辑框架，通过可行性门控和Doob-h变换实现多目标优化与硬约束下的序列编辑，并在GFP、Cas9和肽模拟物上验证了有效性。
AI 中文摘要
生物分子治疗通常从已知序列出发，需要有针对性的编辑以改善多种性质，同时满足严格的生化和可制造性约束。然而，现有的生成方法不能同时支持多目标优化、硬可行性约束以及离散、可变长度生物空间中的序列编辑。在本工作中，我们提出了帕累托约束分子编辑（pCoMole），一个基于离散流匹配的框架，它引导预训练的编辑流（Edit Flow）朝向用户指定的偏好，同时强制终端可行性。pCoMole通过增强的Tchebycheff效用定义了可行性门控的终端分布，并通过底层编辑过程的Doob-h变换实现所得的偏好倾斜。为了使该构造实用，我们使用候选编辑上的短蒙特卡洛滚动来近似所需的调和函数，从而产生具有可证明偏好一致性的高效引导编辑器。我们通过缩小GFP同时保留荧光相关性质、缩短多种Cas9直系同源物同时保持PAM特异性，以及将肽结合物压缩为在硬约束下优化七种药物相关性质的短肽模拟物来验证pCoMole。在湿实验测试中，两个229残基的pCoMole设计的eGFP变体在10次删除后，在BL21细胞中保留了清晰的绿色荧光，且仅有一或两个替换。总之，pCoMole能够在离散、可变长度的生物空间中进行约束感知、帕累托对齐的生物分子序列编辑。
英文摘要
Biomolecular therapeutics often start from known sequences and require targeted editing to improve multiple properties while satisfying hard biochemical and manufacturability constraints. However, existing generative methods do not jointly support multi-objective optimization, hard feasibility, and sequence editing in discrete, variable-length biological spaces. In this work, we introduce Pareto-Constrained Molecule Editing (pCoMole), a framework built on discrete flow matching that steers a pre-trained Edit Flow toward user-specified preferences while enforcing terminal feasibility. pCoMole defines a feasibility-gated terminal distribution using an augmented Tchebycheff utility and realizes the resulting preference tilt through a Doob-h transform of the underlying edit process. To make this construction practical, we approximate the required harmonic function using short Monte Carlo rollouts over candidate edits, yielding an efficient guided editor with provable preference consistency. We validate pCoMole by shrinking GFP while retaining fluorescence-related properties, shortening diverse Cas9 orthologs while preserving PAM specificity, and compressing peptide binders into short peptidomimetics that optimize seven drug-related properties under hard constraints. In wet lab testing, two 229-residue pCoMole-designed eGFP variants retained clear green fluorescence in BL21 cells after 10 deletions, with either one or two substitutions. Together, pCoMole enables constraint-aware, Pareto-aligned editing of biomolecular sequences in discrete, variable-length spaces.
CommentsPublished at NeurIPS 2026. (Proceedings of the 40th Conference on Neural Information Processing Systems, Sydney, Australia)
