用分步细化方式生成蛋白质骨架,像雕刻雕像一样从粗到细构建结构。
Protein Autoregressive Modeling via Multiscale Structure Generation
- 分尺度逐步生成:从粗略拓扑到细节,逐级细化蛋白质骨架。
- 零样本生成表现佳:无需微调即可生成高质量骨架,支持自定义条件生成。
- 解决训练与生成不一致问题:通过噪声上下文学习和调度采样提升稳定性。
我们提出蛋白自回归建模(PAR),首个基于多尺度自回归框架的蛋白质主链生成方法,采用从粗到细的逐级预测策略。利用蛋白质的层次结构特性,PAR模拟雕塑过程:先构建粗略拓扑,再逐步精炼结构细节。其核心包含三部分:(i) 多尺度下采样操作,在训练中表示不同尺度的蛋白结构;(ii) 自回归变换器,编码多尺度信息并生成引导结构生成的条件嵌入;(iii) 基于流的主链解码器,根据嵌入生成主链原子。此外,自回归模型常受暴露偏差困扰,即训练与生成阶段不匹配,严重影响生成质量。为此,我们引入噪声上下文学习和调度采样,有效缓解该问题,实现鲁棒生成。值得注意的是,PAR具备强零样本泛化能力,支持灵活的人类提示条件生成与基序支架构建,无需微调。在无条件生成基准测试中,PAR能有效学习蛋白分布,生成高质量主链,并表现出良好的可扩展性。这些特性使PAR成为蛋白质结构生成的有前景框架。
原文摘要 · Abstract (English)
We present protein autoregressive modeling (PAR), the first multi-scale autoregressive framework for protein backbone generation via coarse-to-fine next-scale prediction. Using the hierarchical nature of proteins, PAR generates structures that mimic sculpting a statue, forming a coarse topology and refining structural details over scales. To achieve this, PAR consists of three key components: (i) multi-scale downsampling operations that represent protein structures across multiple scales during training; (ii) an autoregressive transformer that encodes multi-scale information and produces conditional embeddings to guide structure generation; (iii) a flow-based backbone decoder that generates backbone atoms conditioned on these embeddings. Moreover, autoregressive models suffer from exposure bias, caused by the training and the generation procedure mismatch, and substantially degrades structure generation quality. We effectively alleviate this issue by adopting noisy context learning and scheduled sampling, enabling robust backbone generation. Notably, PAR exhibits strong zero-shot generalization, supporting flexible human-prompted conditional generation and motif scaffolding without requiring fine-tuning. On the unconditional generation benchmark, PAR effectively learns protein distributions and produces backbones of high design quality, and exhibits favorable scaling behavior. Together, these properties establish PAR as a promising framework for protein structure generation.
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