ResNetKhib: a novel cell type-specific tool for predicting lysine 2-hydroxyisobutylation sites via transfer learning

Lysine 2-hydroxyisobutylation (K(hib)), which was first reported in 2014, has been shown to play vital roles in a myriad of biological processes including gene transcription, regulation of chromatin functions, purine metabolism, pentose phosphate pathway and glycolysis/gluconeogenesis. Identification of K(hib) sites in protein substrates represents an initial but crucial step in elucidating the molecular mechanisms underlying protein 2-hydroxyisobutylation. Experimental identification of K(hib) sites mainly depends on the combination of liquid chromatography and mass spectrometry. However, experimental approaches for identifying K(hib) sites are often time-consuming and expensive compared with computational approaches. Previous studies have shown that K(hib) sites may have distinct characteristics for different cell types of the same species. Several tools have been developed to identify K(hib) sites, which exhibit high diversity in their algorithms, encoding schemes and feature selection techniques. However, to date, there are no tools designed for predicting cell type-specific K(hib) sites. Therefore, it is highly desirable to develop an effective predictor for cell type-specific K(hib) site prediction. Inspired by the residual connection of ResNet, we develop a deep learning-based approach, termed ResNetKhib, which leverages both the one-dimensional convolution and transfer learning to enable and improve the prediction of cell type-specific 2-hydroxyisobutylation sites. ResNetKhib is capable of predicting K(hib) sites for four human cell types, mouse liver cell and three rice cell types. Its performance is benchmarked against the commonly used random forest (RF) predictor on both 10-fold cross-validation and independent tests. The results show that ResNetKhib achieves the area under the receiver operating characteristic curve values ranging from 0.807 to 0.901, depending on the cell type and species, which performs better than RF-based predictors and other currently available K(hib) site prediction tools. We also implement an online web server of the proposed ResNetKhib algorithm together with all the curated datasets and trained model for the wider research community to use, which is publicly accessible at https://resnetkhib.erc.monash.edu/.