arXivDaily arXiv每日学术速递 周一至周五更新
2606.14510 2026-06-19 cs.LG q-bio.BM 交叉投稿

PepALD: Macrocyclic Peptide Generation via Autoregressive Latent Diffusion

PepALD: 通过自回归潜在扩散生成大环肽

Junming Zhang, Siyu Yi, Wei Ju, Zhonghui Gu

发表机构 * College of Computer Science, Sichuan University(四川大学计算机科学学院) School of Mathematics, Sichuan University(四川大学数学学院) School of Artificial Intelligence, Sichuan University(四川大学人工智能学院) Lingang Laboratory(临港实验室)

AI总结 提出PepALD模型,结合自回归潜在扩散与化学嵌入,实现从头设计大环肽,并利用偏好优化提升亲和力,在生成质量和奖励优化上优于基线。

Comments 18 pages, 5 figures, 3 tables

详情
AI中文摘要

大环肽是细胞内靶点的有前景的治疗候选物,但其设计需要同时控制非天然单体化学、环拓扑、膜通透性和靶点结合。现有的SMILES或HELM字符串生成模型要么在长原子级序列空间中操作,要么将单体视为具有有限化学基础符号化令牌。我们引入了PepALD,一个用于从头生成大环肽的自回归潜在扩散(ALD)基础模型。该模型使用结构化化学嵌入表示HELM单体,通过在化学信息潜在空间中的上下文条件扩散生成每个残基,在自回归生成过程中预测R基团感知的环闭合,并使用胜者保护的扩散自适应偏好优化将去噪器与亲和力奖励对齐。体外实验表明,PepALD在生成质量和奖励优化性能上优于代表性肽生成基线。

英文摘要

Macrocyclic peptides are promising therapeutic candidates for intracellular targets, but their design requires simultaneous control over non-natural monomer chemistry, ring topology, membrane permeability, and target binding. Existing SMILES- or HELM-string generative models either operate in long atom-level sequence spaces or treat monomers as symbolic tokens with limited chemical grounding. We introduce PepALD, an Autoregressive Latent Diffusion (ALD) foundation model for \textit{de novo} macrocyclic peptide generation. The model represents HELM monomers with structured chemical embeddings, generates each residue through context-conditioned diffusion in chemically informed latent space, predicts R-group-aware ring closures during autoregressive generation, and aligns the denoiser to affinity rewards using winner-protected diffusion-adapted preference optimization. In silico experiments demonstrate PepALD's generation quality and reward-optimization performance against representative peptide generation baselines.