Predicting disease-associated mutation of metal-binding sites in proteins using a deep learning approach

Metalloproteins play important roles in many biological processes. Mutations at the metal-binding sites may functionally disrupt metalloproteins, initiating severe diseases; however, there seemed to be no effective approach to predict such mutations until now. Here we develop a deep learning approach to successfully predict disease-associated mutations that occur at the metal-binding sites of metalloproteins. We generate energy-based affinity grid maps and physiochemical features of the metal-binding pockets (obtained from different databases as spatial and sequential features) and subsequently implement these features into a multichannel convolutional neural network. After training the model, the multichannel convolutional neural network can successfully predict disease-associated mutations that occur at the first and second coordination spheres of zinc-binding sites with an area under the curve of 0.90 and an accuracy of 0.82. Our approach stands for the first deep learning approach for the prediction of disease-associated metal-relevant site mutations in metalloproteins, providing a new platform to tackle human diseases.