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In Computational and mathematical methods in medicine

Water molecules play an important role in many biological processes in terms of stabilizing protein structures, assisting protein folding, and improving binding affinity. It is well known that, due to the impacts of various environmental factors, it is difficult to identify the conserved water molecules (CWMs) from free water molecules (FWMs) directly as CWMs are normally deeply embedded in proteins and form strong hydrogen bonds with surrounding polar groups. To circumvent this difficulty, in this work, the abundance of spatial structure information and physicochemical properties of water molecules in proteins inspires us to adopt machine learning methods for identifying the CWMs. Therefore, in this study, a machine learning framework to identify the CWMs in the binding sites of the proteins was presented. First, by analyzing water molecules' physicochemical properties and spatial structure information, six features (i.e., atom density, hydrophilicity, hydrophobicity, solvent-accessible surface area, temperature B-factors, and mobility) were extracted. Those features were further analyzed and combined to reach a higher CWM identification rate. As a result, an optimal feature combination was determined. Based on this optimal combination, seven different machine learning models (including support vector machine (SVM), K-nearest neighbor (KNN), decision tree (DT), logistic regression (LR), discriminant analysis (DA), naïve Bayes (NB), and ensemble learning (EL)) were evaluated for their abilities in identifying two categories of water molecules, i.e., CWMs and FWMs. It showed that the EL model was the desired prediction model due to its comprehensive advantages. Furthermore, the presented methodology was validated through a case study of crystal 3skh and extensively compared with Dowser++. The prediction performance showed that the optimal feature combination and the desired EL model in our method could achieve satisfactory prediction accuracy in identifying CWMs from FWMs in the proteins' binding sites.

Xiao Wei, Ren Juhui, Hao Jutao, Wang Haoyu, Li Yuhao, Lin Liangzhao