arXiv:2605.23961q-bio.BMcs.AI2026-05

用多模态对齐与偏好优化,生成能精准结合蛋白的新型RNA序列。

Multimodal Alignment and Preference Optimization for Zero-Shot Conditional RNA Generation

论文配图:Multimodal Alignment and Preference Optimization for Zero-Shot Conditional RNA Generation
图 1 · 摘自论文原文
  • 通过多模态微调,让RNA生成模型同时理解蛋白结构和序列特征。
  • 在合成数据上使用直接偏好优化,提升结合亲和力且不破坏自然分布。
  • 生成序列兼具新颖性、多样性与生物合理性,性能超越现有方法。

设计能与特定蛋白结合的RNA分子是实验与计算生物学中的关键挑战。尽管自然语言建模和基于深度学习的蛋白质设计已有进展,但在成功交互频率与生成序列的功能真实性方面仍有提升空间。本文将条件化RNA序列生成视为多阶段对齐问题,提出Moirain:一套通过多模态监督微调(SFT)与直接偏好优化(DPO)训练的模型。首先在大规模多样化RNA语料库上预训练,捕捉序列合理性的基本语法;接着采用多模态SFT架构,以蛋白结构与序列特征为条件生成RNA;最后利用合成交互数据进行DPO优化,借助DPO在非对齐偏好空间中的优势,在不破坏已学自然分布的前提下提升功能适应性。对Moirain系列(Moirain-Base、-Multi、-DPO)的广泛评估表明,该框架持续生成新颖、多样且生物合理的RNA序列,其结合亲和力显著优于现有基线。

原文摘要 · Abstract (English)

The design of RNA molecules that interact with specific proteins is a critical challenge in experimental and computational biology. Despite recent progress in natural language modeling and deep learning-based protein design, there remains significant room to improve the frequency of successful interactions and the authenticity of generated sequences for functional applications. In this work, we frame conditional RNA sequence generation as a multi-stage alignment problem, introducing Moirain: a suite of models optimized via multimodal supervised fine-tuning (SFT) and Direct Preference Optimization (DPO). Our approach begins with large-scale pretraining on diverse RNA corpora to capture the fundamental grammars of sequence plausibility. To achieve target-specific generation, we employ a multimodal SFT architecture that conditions RNA synthesis on protein structural and sequential features. Finally, we leverage DPO to refine the model using synthetic interaction data: taking advantage of DPO's unique ability to navigate non-aligned preference spaces, we improve functional fitness without collapsing the learned natural distribution. Extensive evaluation of the Moirain series (Moirain-Base, -Multi, and -DPO) demonstrates that our framework consistently produces novel, diverse, and biologically plausible RNA sequences with superior binding affinities compared to existing baselines.

RNA生成多模态对齐偏好优化蛋白结合

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