arXiv:2601.19232cs.LGcs.AI2026-01AAAI

用强化学习优化扩散模型,精准设计能折叠成特定三维结构的RNA序列。

Structure-based RNA Design by Step-wise Optimization of Latent Diffusion Model

  • 基于预训练嵌入的隐空间扩散模型,结合强化学习逐步优化结构目标。
  • 在SS、MFE和LDDT三项指标上均超越现有方法,结构准确性显著提升。
  • 适合从事RNA药物设计与合成生物学的研究者,尤其关注结构可控设计。

RNA逆折叠——设计能形成特定3D结构的序列——对治疗、基因调控和合成生物学至关重要。当前方法聚焦于序列恢复,难以兼顾二级结构一致性(SS)、最小自由能(MFE)和局部距离差异测试(LDDT)等结构目标,导致结构精度不足。为此,我们提出一种融合强化学习(RL)与隐空间扩散模型(LDM)的框架。受扩散模型在RNA逆折叠中成功建模复杂序列-结构关系的启发,我们引入大规模RNA模型生成的预训练RNA-FM嵌入,捕捉共进化模式,显著提升序列恢复准确率。然而,现有方法(包括扩散模型)无法有效处理不可微的结构目标。相比之下,强化学习通过策略驱动的奖励优化,在无梯度条件下仍可高效探索复杂目标,具备显著优势。我们提出逐步优化隐空间扩散模型(SOLD),无需采样完整扩散轨迹,即可单步优化噪声,实现多结构目标的高效精炼。实验表明,SOLD在所有指标上均优于其LDM基线及现有最先进方法,为RNA逆折叠提供了强大框架,具有深远的生物技术与治疗应用价值。

原文摘要 · Abstract (English)

RNA inverse folding, designing sequences to form specific 3D structures, is critical for therapeutics, gene regulation, and synthetic biology. Current methods, focused on sequence recovery, struggle to address structural objectives like secondary structure consistency (SS), minimum free energy (MFE), and local distance difference test (LDDT), leading to suboptimal structural accuracy. To tackle this, we propose a reinforcement learning (RL) framework integrated with a latent diffusion model (LDM). Drawing inspiration from the success of diffusion models in RNA inverse folding, which adeptly model complex sequence-structure interactions, we develop an LDM incorporating pre-trained RNA-FM embeddings from a large-scale RNA model. These embeddings capture co-evolutionary patterns, markedly improving sequence recovery accuracy. However, existing approaches, including diffusion-based methods, cannot effectively handle non-differentiable structural objectives. By contrast, RL excels in this task by using policy-driven reward optimization to navigate complex, non-gradient-based objectives, offering a significant advantage over traditional methods. In summary, we propose the Step-wise Optimization of Latent Diffusion Model (SOLD), a novel RL framework that optimizes single-step noise without sampling the full diffusion trajectory, achieving efficient refinement of multiple structural objectives. Experimental results demonstrate SOLD surpasses its LDM baseline and state-of-the-art methods across all metrics, establishing a robust framework for RNA inverse folding with profound implications for biotechnological and therapeutic applications.

RNA设计扩散模型强化学习逆折叠

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