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A High-Performance and Interpretable pKa Prediction Framework Integrating Count-Based Fingerprints and Ensemble
Hui Shen1, Yongquan He2, Juefeng Deng2
1Zhejiang Key Laboratory of Digital Intelligence Monitoring and Restoration of Watershed Environment, College of Geography and Environmental Sciences, Zhejiang Normal University, Jinhua 321004, China.
This study introduces a new machine learning model using count-based Morgan fingerprints for accurate acid dissociation constant (pKa) prediction. The model demonstrates strong generalizability and interpretability, aiding environmental risk assessments.
Area of Science:
- Computational chemistry
- Environmental science
- Machine learning
Background:
- Accurate prediction of acid dissociation constant (pKa) is crucial for understanding organic compound environmental fate.
- Traditional binary Morgan fingerprints (B-MF) lack stoichiometric information, hindering accurate pKa modeling.
- Substituent effects significantly influence pKa, necessitating improved predictive methods.
Purpose of the Study:
- Develop an interpretable machine learning framework for high-performance pKa prediction.
- Integrate count-based Morgan fingerprints (C-MF) to capture functional group multiplicity.
- Enhance pKa prediction accuracy and generalizability for environmental applications.
Main Methods:
- Developed a machine learning framework using count-based Morgan fingerprints (C-MF) and ensemble algorithms.
- Employed SHAP-based recursive feature elimination (SHAP-RFE) for model optimization.
- Defined the applicability domain using the AD_SAL method for reliable predictions.
Main Results:
- Count-based Morgan fingerprints (C-MF) outperformed traditional binary Morgan fingerprints (B-MF).
- The optimized Catboost model achieved high accuracy (test-set R² = 0.890, RMSE = 1.026).
- SHAP analysis confirmed chemically intuitive feature importance and model interpretability.
- External validation demonstrated strong generalizability with R² = 0.890 and RMSE = 0.942.
Conclusions:
- The developed framework provides a robust and generalizable tool for accurate pKa prediction.
- The model's interpretability facilitates understanding of substituent effects on pKa.
- This approach has significant potential for environmental risk assessment and chemical safety evaluations.
