arXiv:2409.16298q-bio.BMcs.LG2024-09被引 4

用强化学习引导扩散模型,高效设计高亲和力抗体序列。

BetterBodies: Reinforcement Learning guided Diffusion for Antibody Sequence Design

  • 结合VAE与强化学习的潜在空间扩散生成抗体序列
  • 在SARS-CoV抗原上实现更高亲和力,优于基线方法
  • 适合生物制药领域快速筛选高活性抗体新结构

抗体在治疗多种疾病方面具有巨大潜力,但传统湿实验方法发现治疗性抗体成本高、耗时长。生成模型可显著缩短研发周期。近期扩散模型因能生成多样且高质量样本而受到关注,但其基本形式缺乏对特定性质(如抗原亲和力)的优化能力。相比之下,离线强化学习在复杂搜索空间中表现优异,尤其适用于难以频繁进行真实世界交互的场景。本文提出BetterBodies方法,将变分自编码器(VAE)与强化学习引导的潜在扩散相结合,从不同数据分布中生成新型抗体CDRH3序列。通过Absolut!模拟器验证,所生成序列对SARS-CoV刺突蛋白受体结合域的亲和力显著提升。此外,利用对比损失在VAE潜在空间中反映生化特性,并引入新型基于Q函数的过滤机制,进一步增强生成序列的亲和力。该方法有望在真实世界生物序列设计中带来重要影响,尤其适用于高亲和力结合剂的低成本构建。

原文摘要 · Abstract (English)

Antibodies offer great potential for the treatment of various diseases. However, the discovery of therapeutic antibodies through traditional wet lab methods is expensive and time-consuming. The use of generative models in designing antibodies therefore holds great promise, as it can reduce the time and resources required. Recently, the class of diffusion models has gained considerable traction for their ability to synthesize diverse and high-quality samples. In their basic form, however, they lack mechanisms to optimize for specific properties, such as binding affinity to an antigen. In contrast, the class of offline Reinforcement Learning (RL) methods has demonstrated strong performance in navigating large search spaces, including scenarios where frequent real-world interaction, such as interaction with a wet lab, is impractical. Our novel method, BetterBodies, which combines Variational Autoencoders (VAEs) with RL guided latent diffusion, is able to generate novel sets of antibody CDRH3 sequences from different data distributions. Using the Absolut! simulator, we demonstrate the improved affinity of our novel sequences to the SARS-CoV spike receptor-binding domain. Furthermore, we reflect biophysical properties in the VAE latent space using a contrastive loss and add a novel Q-function based filtering to enhance the affinity of generated sequences. In conclusion, methods such as ours have the potential to have great implications for real-world biological sequence design, where the generation of novel high-affinity binders is a cost-intensive endeavor.

抗体设计扩散模型强化学习生成模型

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