Identifying Protein Phosphorylation Site-Disease Associations Based on Multi-Similarity Fusion and Negative Sample Selection by Convolutional Neural Network

Abstract

As one of the most important post-translational modifications (PTMs), protein phosphorylation plays a key role in a variety of biological processes. Many studies have shown that protein phosphorylation is associated with various human diseases. Therefore, identifying protein phosphorylation site-disease associations can help to elucidate the pathogenesis of disease and discover new drug targets. Networks of sequence similarity and Gaussian interaction profile kernel similarity were constructed for phosphorylation sites, as well as networks of disease semantic similarity, disease symptom similarity and Gaussian interaction profile kernel similarity were constructed for diseases. To effectively combine different phosphorylation sites and disease similarity information, random walk with restart algorithm was used to obtain the topology information of the network. Then, the diffusion component analysis method was utilized to obtain the comprehensive phosphorylation site similarity and disease similarity. Meanwhile, the reliable negative samples were screened based on the Euclidean distance method. Finally, a convolutional neural network (CNN) model was constructed to identify potential associations between phosphorylation sites and diseases. Based on tenfold cross-validation, the evaluation indicators were obtained including accuracy of 93.48%, specificity of 96.82%, sensitivity of 90.15%, precision of 96.62%, Matthew's correlation coefficient of 0.8719, area under the receiver operating characteristic curve of 0.9786 and area under the precision-recall curve of 0.9836. Additionally, most of the top 20 predicted disease-related phosphorylation sites (19/20 for Alzheimer's disease; 20/16 for neuroblastoma) were verified by literatures and databases. These results show that the proposed method has an outstanding prediction performance and a high practical value.

Keywords: Convolutional neural network; Diseases; Protein phosphorylation site; The Euclidean distance.