1)上海理工大学健康科学与工程学院,上海 200093;2)上海健康医学院医学影像学院,附属嘉定区中心医院,上海 201318;3)上海健康医学院协同科研中心,上海 201318
上海市科技委员会地方高校能力建设项目(23010502700),上海市“科技创新行动计划”优秀学术/技术带头人计划基金(22XD1401300)和国家自然科学基金(61971275,81830052,82072228,62376152)资助。
1)School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China;2)College of Medical Imaging, Affiliated Jiading District Central Hospital, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China;3)Collaborative Innovation Center, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
The work was supported by grants from Shanghai Municipal Commission of Science and Technology for Capacity Building for Local Universities (23010502700), the Foundation of the Program of Shanghai Academic/Technology Research Leader under the Science and Technology Innovation Action Plan (22XD1401300), and The National Natural Science Foundation of China (61971275, 81830052, 82072228, 62376152).
目的 非编码RNA(non-coding RNA,ncRNA)在多种生命过程中发挥着重要的调控作用,二级结构对于其正常功能实现至关重要。现有的方法在预测RNA二级结构时普遍存在模型复杂度高、难以捕获长程依赖关系以及在复杂结构预测上泛化能力差的问题。因此,需要提出新的方法来预测RNA二级结构。方法 本研究提出一种端到端预测模型RMDfold,使用 残差Mamba(residual Mamba,resMamba)与密集连接(dense connection,Dense)相结合的特征提取策略。模型采用一维和二维两阶段的学习过程进行特征建模,在一维序列空间中学习核苷酸间的依赖关系,再将其映射到二维空间进一步学习核苷酸间的配对模式,并通过配对约束确定核苷酸的唯一配对,得到最终的二级结构。在一维与二维阶段中均通过Dense捕捉短程依赖特征,resMamba建模长程依赖关系,实现信息表征的逐级增强与短长程特征的有效融合。为了验证本方法的有效性,与Ufold、REDfold、TransUfold和sincfold四种方法在RNAStralign、ArchiveII和bpRNA-new三个公开数据集上进行了比较。结果 本研究所提出的RMDfold方法在结构预测、假结预测、不同长度的序列预测和模型复杂度分析上优于其他算法,并且所需参数最少且推理速度最快。在结构预测中,该方法在RNAStralign的F1分数(F1 score,F1)、马修斯相关系数(Matthews correlation coefficient,MCC)、精确度(precision)和召回率(recall)分别达到0.973 5、0.973 1、0.975 6和0.972 3,在ArchiveII的F1、MCC、precision和recall分别达到0.854 3、0.855 6、0.874 7和0.876 2,在bpRNA-new的F1、MCC、precision和recall分别达到0.382 8、0.401 5、0.536 5和0.318 7。在假结预测中,基于ArchiveII数据集,模型的F1、MCC、precision和recall分别达到0.741 4、0.743 3、0.752 5和0.739 6。在不同长度的序列预测中,该方法在200~500 nt序列中仍保持0.70的准确率。在模型复杂度分析中,RMDfold所需参数量为2.886 7 M,推理速度为0.026 0 s。结论 RMDfold能够准确预测RNA的二级结构,有助于揭示RNA分子在基因表达调控、分子识别和催化中的核心作用,也为疾病相关变异机制解析、RNA靶向药物设计以及进化与比较基因组学研究提供重要支持。
Objective Non-coding RNA (ncRNA) plays a crucial regulatory role in various biological processes. Numerous studies have shown that the functions of ncRNAs depend not only on their nucleotide sequences but also closely on their spatial conformations, particularly their secondary structures. Traditional methods for predicting RNA secondary structures often have low accuracy, usually around 50 to 70 percent, and their performance further declines when dealing with complex structures or long sequences. Although deep learning methods have improved prediction performance to some extent, they still face challenges such as high model complexity, difficulty in capturing long-range dependencies, and poor generalization in predicting complex structures. Therefore, it is necessary for RNA secondary structure prediction to develop new methods.Methods This study proposed an end-to-end prediction model RMDfold, which employed a feature extraction strategy combining residual Mamba (resMamba) and dense connections (Dense). The model framework consisted of three modules: one-dimensional (1D) modeling, feature mapping, and two-dimensional (2D) modeling. For the 1D modeling module, the model learned contextual dependencies among nucleotides from RNA sequences, providing the foundation for possible base-pairing; for the feature mapping module, the 1D features were projected into a 2D space to form a constraint matrix that represented potential base-pairing relationships; for the 2D modeling module, the model further learned the pairing patterns between nucleotides, and determined the unique pairing of each nucleotide through pairing constraints, to obtain the final secondary structure. For both 1D and 2D modeling modules, a four-layer Dense block composed of batch normalization, ReLU activation, and convolution was used to extract short-range features; and a dual-branch residual structure resMamba based on a state-space model was used to model long-range dependencies, thereby achieving effective integration of short- and long-range features. To validate the effectiveness of the proposed method, it was compared with Ufold, REDfold, TransUfold, and sincfold on the three public datasets RNAStralign, ArchiveII, and bpRNA-new.Results The proposed RMDfold method demonstrates superior performance compared with existing algorithms in structure prediction, pseudoknot prediction, sequence prediction across varying lengths, and model complexity analysis, while requiring fewer parameters and achieving faster inference. For the structure prediction, the method achieved F1, Matthews correlation coefficient (MCC), precision and recall of 0.973 5, 0.973 1, 0.975 6 and 0.972 3 on RNAStralign, 0.854 3, 0.855 6, 0.874 7 and 0.876 2 on ArchiveII, and 0.382 8, 0.401 5, 0.536 5 and 0.318 7 on bpRNA-new, respectively. For the pseudoknot prediction based on ArchiveII, the model achieved F1, MCC, precision and recall of 0.741 4, 0.743 3, 0.752 5 and 0.739 6. For the sequence prediction across different lengths, RMDfold maintained an accuracy of 0.70 for sequences ranging from 200 to 500 nt. In terms of model complexity, RMDfold required 2.886 7 M parameters and achieves an inference speed of 0.026 0 s.Conclusion RMDfold enables highly accurate prediction of RNA secondary structures. It helps to deeply and comprehensively reveal the central roles of RNA molecules in gene expression regulation, molecular recognition, and catalysis. and also provides important structure support for elucidating disease-related variant mechanisms, designing RNA-targeted drugs, and advancing research in evolution and comparative genomics.
郝泽洲,羊艳玲,周亮,姚旭峰. RMDfold:基于残差Mamba和密集连接的端到端RNA二级结构预测方法[J].生物化学与生物物理进展,2025,52(12):3149-3164 HAO Ze-Zhou, YANG Yan-Ling, ZHOU Liang, YAO Xu-Feng. RMDfold: an End-to-end RNA Secondary Structure Prediction Method Based on Residual Mamba and Dense Connections[J]. Progress in Biochemistry and Biophysics,2025,52(12):3149-3164
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