Machine learning-based approaches for ubiquitination site prediction in human proteins.

Protein ubiquitination is a critical post-translational modification (PTMs) involved in numerous cellular processes. Identifying ubiquitination sites (Ubi-sites) on proteins offers valuable insights into their function and regulatory mechanisms. Due to the cost- and time-consuming nature of traditional approaches for Ubi-site detection, there has been a growing interest in leveraging artificial intelligence for computer-aided Ubi-site prediction. In this study, we collected experimentally verified Ubi-sites of human proteins from the dbPTM database, then conducted comprehensive state-of-the art computational methods along with standard evaluation metrics and a proper validation strategy for Ubi-site prediction. We presented the effectiveness of our framework by comparing ten machine learning (ML) based approaches in three different categories: feature-based conventional ML methods, end-to-end sequence-based deep learning (DL) techniques, and hybrid feature-based DL models. Our results revealed that DL approaches outperformed the classical ML methods, achieving a 0.902 F1-score, 0.8198 accuracy, 0.8786 precision, and 0.9147 recall as the best performance for a DL model using both raw amino acid sequences and hand-crafted features. Interestingly, our experimental results disclosed that the performance of DL methods had a positive correlation with the length of amino acid fragments, suggesting that utilizing the entire sequence can lead to more accurate predictions in future research endeavors. Additionally, we developed a meticulously curated benchmark for Ubi-site prediction in human proteins. This benchmark serves as a valuable resource for future studies, enabling fair and accurate comparisons between different methods. Overall, our work highlights the potential of ML, particularly DL techniques, in predicting Ubi-sites and furthering our knowledge of protein regulation through ubiquitination in cells.

S-PLM: Structure-aware Protein Language Model via Contrastive Learning between Sequence and Structure.

Large protein language models (PLMs) present excellent potential to reshape protein research by encoding the amino acid sequences into mathematical and biological meaningful embeddings. However, the lack of crucial 3D structure information in most PLMs restricts the prediction capacity of PLMs in various applications, especially those heavily depending on 3D structures. To address this issue, we introduce S-PLM, a 3D structure-aware PLM utilizing multi-view contrastive learning to align the sequence and 3D structure of a protein in a coordinate space. S-PLM applies Swin-Transformer on AlphaFold-predicted protein structures to embed the structural information and fuses it into sequence-based embedding from ESM2. Additionally, we provide a library of lightweight tuning tools to adapt S-PLM for diverse protein property prediction tasks. Our results demonstrate S-PLM's superior performance over sequence-only PLMs, achieving competitiveness in protein function prediction compared to state-of-the-art methods employing both sequence and structure inputs.

A Review of Machine Learning and Algorithmic Methods for Protein Phosphorylation Site Prediction.

Post-translational modifications (PTMs) have key roles in extending the functional diversity of proteins and, as a result, regulating diverse cellular processes in prokaryotic and eukaryotic organisms. Phosphorylation modification is a vital PTM that occurs in most proteins and plays a significant role in many biological processes. Disorders in the phosphorylation process lead to multiple diseases, including neurological disorders and cancers. The purpose of this review is to organize this body of knowledge associated with phosphorylation site (p-site) prediction to facilitate future research in this field. At first, we comprehensively review all related databases and introduce all steps regarding dataset creation, data preprocessing, and method evaluation in p-site prediction. Next, we investigate p-site prediction methods, which are divided into two computational groups: algorithmic and machine learning (ML). Additionally, it is shown that there are basically two main approaches for p-site prediction by ML: conventional and end-to-end deep learning methods, both of which are given an overview. Moreover, this review introduces the most important feature extraction techniques, which have mostly been used in p-site prediction. Finally, we create three test sets from new proteins related to the released version of the database of protein post-translational modifications (dbPTM) in 2022 based on general and human species. Evaluating online p-site prediction tools on newly added proteins introduced in the dbPTM 2022 release, distinct from those in the dbPTM 2019 release, reveals their limitations. In other words, the actual performance of these online p-site prediction tools on unseen proteins is notably lower than the results reported in their respective research papers.