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arXiv 2601.19232cs.LGcs.AI
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基于结构的RNA设计:通过潜在扩散模型的分步优化

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

Qi Si, Xuyang Liu, Penglei Wang, Xin Guo, Yuan Qi, Yuan Cheng

AI总结:

本文提出SOLD框架,通过强化学习优化潜在扩散模型,提升RNA结构设计的准确性与效率。

摘要:

RNA逆折叠,即设计序列以形成特定三维结构,对于治疗、基因调控和合成生物学至关重要。当前方法专注于序列恢复,难以处理结构目标,如二级结构一致性(SS)、最小自由能(MFE)和局部距离差测试(LDDT),导致结构准确性不理想。为此,我们提出了一种结合潜在扩散模型(LDM)的强化学习(RL)框架。受扩散模型在RNA逆折叠中的成功启发,我们开发了包含预训练的RNA-FM嵌入的LDM,这些嵌入来自大规模RNA模型,能够捕捉共进化模式,显著提高序列恢复准确性。然而,现有方法,包括基于扩散的方法,无法有效处理非可微结构目标。相比之下,RL在这一任务中表现出色,通过策略驱动的奖励优化来导航复杂的非梯度目标,相较于传统方法具有显著优势。总之,我们提出了一种名为“潜在扩散模型的分步优化”(SOLD)的新型RL框架,通过优化单步噪声而不采样完整的扩散轨迹,实现了多个结构目标的有效细化。实验结果表明,SOLD在所有指标上均优于其LDM基线和最先进的方法,建立了RNA逆折叠的稳健框架,对生物技术和治疗应用具有深远影响。

英文摘要:

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.

机构、总结、中文摘要均由AI分析而来,可能存在错误,请以论文正文为准。

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