Papers › Topological Machine Learning for Protein-Nucleic Acid Binding Affinity Changes Upon Mutation

Topological Machine Learning for Protein-Nucleic Acid Binding Affinity Changes Upon Mutation

28 May 2025arXiv:2505.22786archive 2025-07-28

Xiang Liu, JunJie Wee, Guo-Wei Wei

Understanding how protein mutations affect protein-nucleic acid binding is critical for unraveling disease mechanisms and advancing therapies. Current experimental approaches are laborious, and computational methods remain limited in accuracy. To address this challenge, we propose a novel topological machine learning model (TopoML) combining persistent Laplacian (from topological data analysis) with multi-perspective features: physicochemical properties, topological structures, and protein Transformer-derived sequence embeddings. This integrative framework captures robust representations of protein-nucleic acid binding interactions. To validate the proposed method, we employ two datasets, a protein-DNA dataset with 596 single-point amino acid mutations, and a protein-RNA dataset with 710 single-point amino acid mutations. We show that the proposed TopoML model outperforms state-of-the-art methods in predicting mutation-induced binding affinity changes for protein-DNA and protein-RNA complexes.

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Topological Data Analysis

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