This paper is available on under CC 4.0 license. Arxiv Authors: (1) Md Masud Rana, Department of Mathematics, University of Kentucky; (2) Duc Duy Nguyen, Department of Mathematics, University of Kentucky & ducnguyen@uky.edu. Table of Links Abstract & Introduction Datasets and Results Methods Conclusion, Data and Software Availability, Competing interests, Acknowledgments & References 4 Conclusion The study of protein-protein interactions (PPIs) and the prediction of mutation-induced binding free energy changes are of great importance in understanding the molecular basis of biological processes. The application of geometric graph theory and atom-level graph coloring techniques provides a powerful framework for analyzing biomolecules and capturing their intricate relationships. By utilizing the concept of geometric subgraphs and constructing multi-scale weighted colored geometric subgraphs (MWCGS), we can effectively represent the structural and functional properties of PPIs. The site-specific MWCGS features allow us to extract meaningful patterns and characteristics, shedding light on the effects of mutations and the underlying molecular interactions. In this work, we developed a mutation-induced binding free energy change predictor, called GGL-PPI, by incorporating site-specific MWCGS features for PPIs and gradient-boosting trees. Our method demonstrates superior performance compared to existing methods. The model was validated on three datasets: AB-Bind S645, SKEMPI 1.0 S1131, and SKEMPI 2.0 S4169 and S8338, showcasing its robustness and effectiveness. Furthermore, GGL-PPI was evaluated on a blind test set, the Ssym dataset. To prevent data leakage between the test and training sets, the model was trained on a homology-reduced balanced training set Q3488. This approach ensures the reliability and fairness of the evaluation process. GGL-PPI exhibits the most unbiased and superior performance in predicting binding free energy changes for both direct and reverse mutations, outperforming other existing methods, particularly for reverse mutations. Overall, the results highlight the potential of the GGL-PPI approach in accurately predicting mutation-induced binding free energy changes in protein-protein interactions, providing valuable insights into the molecular mechanisms underlying protein-protein interactions and facilitating drug design and discovery efforts. 5 Data and Software Availability The source code is available at Github: https://github.com/NguyenLabUKY/GGL-Mutation. 6 Competing interests No competing interest is declared. 7 Acknowledgments This work is supported in part by funds from the National Science Foundation (NSF: # 2053284, # 2151802, and # 2245903), and the University of Kentucky Startup Fund. References [1] Dana Chuderland and Rony Seger. 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PPIs and the Prediction of Mutation-Induced Binding Free Energy Changes: What It All Means

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