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3D-ΔΔG:一种基于蛋白质三维结构预测突变后蛋白质-蛋白质结合亲和力变化的双通道预测模型。

3D-ΔΔG: A Dual-Channel Prediction Model for Protein-Protein Binding Affinity Changes Following Mutation Based on Protein 3D Structures.

作者信息

Wang Yuxiang, Zhu Yibo, Shi Xiumin, Wang Lu

机构信息

School of Information and Electronics, Beijing Institute of Technology, Beijing, China.

Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China.

出版信息

Proteins. 2025 May 15. doi: 10.1002/prot.26837.

Abstract

Protein-protein interactions are crucial for cellular regulation, antigen-antibody interactions, and other vital processes within living organisms. However, mutations in amino acid residues have the potential to induce changes in protein-protein binding affinity (ΔΔG), which may contribute to the onset and progression of disease. Existing methods for predicting ΔΔG use either protein sequence information or structural data. Furthermore, some methods are only applicable to single-point mutation cases. To address these limitations, we introduce a ΔΔG predictor that can handle complex scenarios involving multipoint mutations. In this investigation, a dual-channel deep learning model three-dimensional (3D)-ΔΔG is introduced, which is designed to predict ΔΔG by combining mutation information from side chain sequences and 3D structures. The proposed model employs a pre-trained protein language model to encode the side-chain amino acid sequence. A graph attention network is deployed to handle the graph representation of proteins simultaneously. Finally, a dual-channel processing module is implemented to facilitate depth fusion and extraction of both sequence and structural features. The model effectively captures the intricate alterations occurring pre- and post-protein mutation by integrating both sequence and 3D structural information. Results on the single-point mutation data set demonstrate a substantial improvement compared to state-of-the-art models. More significantly, 3D-ΔΔG exhibits superior performance when evaluated on the mixed mutation data sets, SKEMPIv1 and SKEMPIv2. The high level of agreement between the computationally predicted ΔΔG values and the experimentally determined values illustrates the potential of the 3D-ΔΔG model as an effective pre-screening tool in protein design and engineering.

摘要

蛋白质-蛋白质相互作用对于细胞调节、抗原-抗体相互作用以及生物体内的其他重要过程至关重要。然而,氨基酸残基的突变有可能导致蛋白质-蛋白质结合亲和力(ΔΔG)的变化,这可能有助于疾病的发生和发展。现有的预测ΔΔG的方法要么使用蛋白质序列信息,要么使用结构数据。此外,一些方法仅适用于单点突变情况。为了解决这些局限性,我们引入了一种能够处理涉及多点突变的复杂情况的ΔΔG预测器。在本研究中,引入了一种双通道深度学习模型三维(3D)-ΔΔG,其设计目的是通过结合来自侧链序列和3D结构的突变信息来预测ΔΔG。所提出的模型采用预训练的蛋白质语言模型对侧链氨基酸序列进行编码。部署了一个图注意力网络来同时处理蛋白质的图表示。最后,实现了一个双通道处理模块,以促进序列和结构特征的深度融合与提取。该模型通过整合序列和3D结构信息,有效地捕捉了蛋白质突变前后发生的复杂变化。单点突变数据集的结果表明,与现有最先进的模型相比有了显著改进。更重要的是,在混合突变数据集SKEMPIv1和SKEMPIv2上进行评估时,3D-ΔΔG表现出卓越的性能。计算预测的ΔΔG值与实验测定值之间的高度一致性说明了3D-ΔΔG模型作为蛋白质设计和工程中一种有效预筛选工具的潜力。

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