arXiv:2511.07390cs.LGq-bio.QM2025-11被引 7

用扩散模型智能删减蛋白序列,保持功能还更像自然演化产物。

A Diffusion Model to Shrink Proteins While Maintaining Their Function

  • 基于扩散模型逆向删除氨基酸,模拟自然序列演化过程。
  • 在ProteinGym上预测删除功能影响达当前最优水平。
  • 适合需要简化蛋白结构但保留功能的生物工程研究者。

许多在现代医学或生物工程中有用的蛋白质因序列过长,难以实验室合成、细胞内融合或体内递送。传统缩短序列依赖耗时昂贵的实验。我们提出SCISOR,一种离散扩散模型,通过从自然序列中随机插入噪声并训练去噪器逆向删除,生成类似自然序列的短蛋白。该模型在拟合进化序列数据方面表现媲美大型预训练模型。在ProteinGym上的评估显示其对删除功能影响的预测达到当前最优。进一步应用中,SCISOR提出的删减方案生成的蛋白更接近真实自然序列,且更有效地保留了关键功能基序。

原文摘要 · Abstract (English)

Many proteins useful in modern medicine or bioengineering are challenging to make in the lab, fuse with other proteins in cells, or deliver to tissues in the body, because their sequences are too long. Shortening these sequences typically involves costly, time-consuming experimental campaigns. Ideally, we could instead use modern models of massive databases of sequences from nature to learn how to propose shrunken proteins that resemble sequences found in nature. Unfortunately, these models struggle to efficiently search the combinatorial space of all deletions, and are not trained with inductive biases to learn how to delete. To address this gap, we propose SCISOR, a novel discrete diffusion model that deletes letters from sequences to generate protein samples that resemble those found in nature. To do so, SCISOR trains a de-noiser to reverse a forward noising process that adds random insertions to natural sequences. As a generative model, SCISOR fits evolutionary sequence data competitively with previous large models. In evaluation, SCISOR achieves state-of-the-art predictions of the functional effects of deletions on ProteinGym. Finally, we use the SCISOR de-noiser to shrink long protein sequences, and show that its suggested deletions result in significantly more realistic proteins and more often preserve functional motifs than previous models of evolutionary sequences.

蛋白质设计扩散模型序列优化

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