Protein function prediction is crucial for understanding species evolution, including viral mutations. Gene ontology (GO) is a standardized representation framework for describing protein functions with annotated terms. Each ontology is a specific functional category containing multiple child ontologies, and the relationships of parent and child ontologies create a directed acyclic graph. Protein functions are categorized using GO, which divides them into three main groups: cellular component ontology, molecular function ontology, and biological process ontology. Therefore, the GO annotation of protein is a hierarchical multilabel classification problem. This hierarchical relationship introduces complexities such as mixed ontology problem, leading to performance bottlenecks in existing computational methods due to label dependency and data sparsity. To overcome bottleneck issues brought by mixed ontology problem, we propose ProFun-SOM, an innovative multilabel classifier that utilizes multiple sequence alignments (MSAs) to accurately annotate gene ontologies. ProFun-SOM enhances the initial MSAs through a reconstruction process and integrates them into a deep learning architecture. It then predicts annotations within the cellular component, molecular function, biological process, and mixed ontologies. Our evaluation results on three datasets (CAFA3, SwissProt, and NetGO2) demonstrate that ProFun-SOM surpasses state-of-the-art methods. This study confirmed that utilizing MSAs of proteins can effectively overcome the two main bottlenecks issues, label dependency and data sparsity, thereby alleviating the root problem, mixed ontology. A freely accessible web server is available at http://bliulab.net/ ProFun-SOM/.

Protein remote homology detection is essential for structure prediction, function prediction, disease mechanism understanding, etc. The remote homology relationship depends on multiple protein properties, such as structural information and local sequence patterns. Previous studies have shown the challenges for predicting remote homology relationship by protein features at sequence level (e.g. position-specific score matrix). Protein motifs have been used in structure and function analysis due to their unique sequence patterns and implied structural information. Therefore, designing a usable architecture to fuse multiple protein properties based on motifs is urgently needed to improve protein remote homology detection performance. To make full use of the characteristics of motifs, we employed the language model called the protein cubic language model (PCLM). It combines multiple properties by constructing a motif-based neural network. Based on the PCLM, we proposed a predictor called PreHom-PCLM by extracting and fusing multiple motif features for protein remote homology detection. PreHom-PCLM outperforms the other state-of-the-art methods on the test set and independent test set. Experimental results further prove the effectiveness of multiple features fused by PreHom-PCLM for remote homology detection. Furthermore, the protein features derived from the PreHom-PCLM show strong discriminative power for proteins from different structural classes in the high-dimensional space. Availability and Implementation: http://bliulab.net/PreHom-PCLM.

Protein remote homology detection is one of fundamental research tasks for downstream analysis (i.e., protein structure and function prediction). Many advanced methods are proposed from different views with complementary detection ability, such as the classification method, the network method, and the ranking method. A framework integrating these heterogeneous methods is urgently desired to reduce the false positive rate and predictive bias. We propose a novel ranking method called ProtRe-CN by fusing the classification methods and network methods via Learning to Rank. Experimental results on the benchmark dataset and the independent dataset show that ProtRe-CN outperforms other existing state-of-the-art predictors. ProtRe-CN improves the detective performance via correcting the false positives in the ranking list by combining the heterogeneous methods. The web server of ProtRe-CN can be accessed at http://bliulab.net/ProtRe-CN.

As one of the most important tasks in protein structure prediction, protein fold recognition has attracted more and more attention. In this regard, some computational predictors have been proposed with the development of machine learning and artificial intelligence techniques. However, these existing computational methods are still suffering from some disadvantages. In this regard, we propose a new network-based predictor called ProtFold-DFG for protein fold recognition. We propose the Directed Fusion Graph (DFG) to fuse the ranking lists generated by different methods, which employs the transitive closure to incorporate more relationships among proteins and uses the KL divergence to calculate the relationship between two proteins so as to improve its generalization ability. Finally, the PageRank algorithm is performed on the DFG to accurately recognize the protein folds by considering the global interactions among proteins in the DFG. Tested on a widely used and rigorous benchmark data set, LINDAHL dataset, experimental results show that the ProtFold-DFG outperforms the other 35 competing methods, indicating that ProtFold-DFG will be a useful method for protein fold recognition. The source code and data of ProtFold-DFG can be downloaded from http://bliulab.net/ProtFold-DFG/download.

As a key for studying the protein structures, protein fold recognition is playing an important role in predicting the protein structures associated with COVID-19 and other important structures. However, the existing computational predictors only focus on the protein pairwise similarity or the similarity between two groups of proteins from 2-folds. However, the homology relationship among proteins is in a hierarchical structure. The global protein similarity network will contribute to the performance improvement. In this study, we proposed a predictor called FoldRec-C2C to globally incorporate the interactions among proteins into the prediction. For the FoldRec-C2C predictor, protein fold recognition problem is treated as an information retrieval task in nature language processing. The initial ranking results were generated by a surprised ranking algorithm Learning to Rank, and then three re-ranking algorithms were performed on the ranking lists to adjust the results globally based on the protein similarity network, including seq-to-seq model, seq-to-cluster model and cluster-to-cluster model (C2C). When tested on a widely used and rigorous benchmark dataset LINDAHL dataset, FoldRec-C2C outperforms other 34 state-of-the-art methods in this field. The source code and data of FoldRec-C2C can be downloaded from http://bliulab.net/FoldRec-C2C/download.