arXiv:2410.13782cs.LGq-bio.QM2024-10ICLR被引 79

DPLM-2 能同时生成蛋白质序列和3D结构,无需分步处理。

DPLM-2: A Multimodal Diffusion Protein Language Model

  • 用无查找表量化将3D坐标转为离散符号,让语言模型学结构
  • 在实验与合成结构上训练,实现序列与结构联合生成
  • 适合需要结构-序列协同设计的研究者,如蛋白工程

蛋白质由氨基酸序列决定其三维结构和功能。现有方法多用独立模型处理序列或结构,难以捕捉二者关联。本文提出DPLM-2,基于离散扩散蛋白语言模型扩展为多模态基础模型,通过无查找表的量化方式将3D坐标转换为离散令牌,使语言模型可学习结构信息。模型在实验与高质量合成结构上联合训练,学习序列与结构的联合分布、边缘分布及条件分布。采用高效预热策略,利用大规模进化数据与序列模型中的结构先验。实验证明,DPLM-2可直接生成高度兼容的序列与3D结构,无需两阶段流程;在折叠、逆折叠、支架构建等条件生成任务中表现优异,并提供可用于预测任务的结构感知表示。

原文摘要 · Abstract (English)

Proteins are essential macromolecules defined by their amino acid sequences, which determine their three-dimensional structures and, consequently, their functions in all living organisms. Therefore, generative protein modeling necessitates a multimodal approach to simultaneously model, understand, and generate both sequences and structures. However, existing methods typically use separate models for each modality, limiting their ability to capture the intricate relationships between sequence and structure. This results in suboptimal performance in tasks that requires joint understanding and generation of both modalities. In this paper, we introduce DPLM-2, a multimodal protein foundation model that extends discrete diffusion protein language model (DPLM) to accommodate both sequences and structures. To enable structural learning with the language model, 3D coordinates are converted to discrete tokens using a lookup-free quantization-based tokenizer. By training on both experimental and high-quality synthetic structures, DPLM-2 learns the joint distribution of sequence and structure, as well as their marginals and conditionals. We also implement an efficient warm-up strategy to exploit the connection between large-scale evolutionary data and structural inductive biases from pre-trained sequence-based protein language models. Empirical evaluation shows that DPLM-2 can simultaneously generate highly compatible amino acid sequences and their corresponding 3D structures eliminating the need for a two-stage generation approach. Moreover, DPLM-2 demonstrates competitive performance in various conditional generation tasks, including folding, inverse folding, and scaffolding with multimodal motif inputs, as well as providing structure-aware representations for predictive tasks.

蛋白质生成多模态扩散模型结构建模

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