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

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.