无需结构预测,直接生成新肽段结合子。
PepEDiff: Zero-Shot Peptide Binder Design via Protein Embedding Diffusion
- 基于预训练蛋白嵌入空间的扩散采样生成肽段。
- 在TIGIT靶点上超越现有方法,实现零样本设计。
- 适合药物研发中快速探索未知结合序列。
我们提出PepEDiff,一种新型肽段结合子生成模型,可在给定目标受体蛋白序列及其口袋残基的情况下,直接生成结合序列。肽段结合子设计对治疗与生化应用至关重要,但现有方法多依赖中间结构预测,增加复杂性并限制序列多样性。本方法摒弃该范式,直接在预训练蛋白嵌入模型导出的连续潜在空间中生成结合序列,不依赖预测结构,从而提升结构与序列多样性。为避免模型仅记忆已知序列,我们采用潜在空间探索与基于扩散的采样策略,使生成肽段超出已知结合子分布。该零样本生成策略利用蛋白嵌入流形作为语义先验,可在蛋白空间未见区域提出新颖肽段。我们在具有挑战性的TIGIT靶点(大而平坦的蛋白-蛋白相互作用界面,无成药口袋)上进行评估,尽管方法简洁,仍优于现有最优方法,在基准测试与案例研究中表现突出,展示了其作为通用、无结构依赖的零样本肽段结合子设计框架的潜力。代码已开源:https://github.com/LabJunBMI/PepEDiff-An-Peptide-binder-Embedding-Diffusion-Model。
原文摘要 · Abstract (English)
We present PepEDiff, a novel peptide binder generator that designs binding sequences given a target receptor protein sequence and its pocket residues. Peptide binder generation is critical in therapeutic and biochemical applications, yet many existing methods rely heavily on intermediate structure prediction, adding complexity and limiting sequence diversity. Our approach departs from this paradigm by generating binder sequences directly in a continuous latent space derived from a pretrained protein embedding model, without relying on predicted structures, thereby improving structural and sequence diversity. To encourage the model to capture binding-relevant features rather than memorizing known sequences, we perform latent-space exploration and diffusion-based sampling, enabling the generation of peptides beyond the limited distribution of known binders. This zero-shot generative strategy leverages the global protein embedding manifold as a semantic prior, allowing the model to propose novel peptide sequences in previously unseen regions of the protein space. We evaluate PepEDiff on TIGIT, a challenging target with a large, flat protein-protein interaction interface that lacks a druggable pocket. Despite its simplicity, our method outperforms state-of-the-art approaches across benchmark tests and in the TIGIT case study, demonstrating its potential as a general, structure-free framework for zero-shot peptide binder design. The code for this research is available at GitHub: https://github.com/LabJunBMI/PepEDiff-An-Peptide-binder-Embedding-Diffusion-Model
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