用生成模型解析DNA反应机理和冷冻电镜图像,让生物数据更可读。
Applications of deep generative models to DNA reaction kinetics and to cryogenic electron microscopy

- 融合生物物理知识与变分自编码器,生成可解释的DNA反应嵌入
- 实现三维反应轨迹降维可视化,揭示新反应路径
- 适合生物物理、结构生物学研究者参考
本论文探索深度生成模型如何结合领域知识推进复杂生物问题分析,聚焦于DNA反应动力学与冷冻电镜(cryo-EM)两个方向。第一部分提出ViDa框架,利用变分自编码器(VAEs)与几何散射变换,生成符合生物物理规律的DNA反应动力学模拟嵌入,将高维轨迹降维至二维空间,用于可视化DNA杂交与发夹介导的链置换反应;该方法保持结构特征并聚类轨迹,揭示反应路径,提升模拟结果可解释性。第二部分针对cryo-EM密度图解读与蛋白质结构建模挑战,系统综述并基准测试深度学习原子模型构建方法,改进评估指标与实用指南。随后提出Struc2mapGAN,一种生成对抗网络,从蛋白质结构合成高保真实验类冷冻电镜密度图。最后提出CryoSAMU,一种结构感知多模态U-Net,通过交叉注意力融合密度特征与蛋白语言模型生成的结构嵌入,提升中等分辨率冷冻电镜图的质量。整体表明深度生成模型在解析DNA反应机制与推动冷冻电镜分析方面具有潜力。
原文摘要 · Abstract (English)
This dissertation explores how deep generative models can advance the analysis of challenging biological problems by integrating domain knowledge with deep learning. It focuses on two areas: DNA reaction kinetics and cryogenic electron microscopy (cryo-EM). In the first part, we present ViDa, a biophysics-informed framework leveraging variational autoencoders (VAEs) and geometric scattering transforms to generate biophysically-plausible embeddings of DNA reaction kinetics simulations. These embeddings are reduced to a two-dimensional space to visualize DNA hybridization and toehold-mediated strand displacement reactions. ViDa preserves structure and clusters trajectory ensembles into reaction pathways, making simulation results more interpretable and revealing new mechanistic insights. In the second part, we address key challenges in cryo-EM density map interpretation and protein structure modeling. We provide a comprehensive review and benchmarking of deep learning methods for atomic model building, with improved evaluation metrics and practical guidance. We then present Struc2mapGAN, a generative adversarial network that synthesizes high-fidelity experimental-like cryo-EM density maps from protein structures. Finally, we present CryoSAMU, a structure-aware multimodal U-Net that enhances intermediate-resolution cryo-EM maps by integrating density features with structural embeddings from protein language models via cross-attention. Overall, these contributions demonstrate the potential of deep generative models to interpret DNA reaction mechanisms and advance cryo-EM density map analysis and protein structure modeling.
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