Viruses pose a great threat to human production and life, thus the research and development of antiviral drugs is urgently needed. Antiviral peptides play an important role in drug design and development. Compared with the time-consuming and laborious wet chemical experiment methods, it is critical to use computational methods to predict antiviral peptides accurately and rapidly. However, due to limited data, accurate prediction of antiviral peptides is still challenging and extracting effective feature representations from sequences is crucial for creating accurate models. This study introduces a novel two-step approach, named HybAVPnet, to predict antiviral peptides with a hybrid network architecture based on neural networks and traditional machine learning methods. We adopted a stacking-like structure to capture both the long-term dependencies and local evolution information to achieve a comprehensive and diverse prediction using the predicted labels and probabilities. Using an ensemble technique with the different kinds of features can reduce the variance without increasing the bias. The experimental result shows HybAVPnet can achieve better and more robust performance compared with the state-of-the-art methods, which makes it useful for the research and development of antiviral drugs. Meanwhile, it can also be extended to other peptide recognition problems because of its generalization ability.

MOTIVATION: Protein structure prediction has been greatly improved by deep learning, but the contribution of different information is yet to be fully understood. This article studies the impacts of two kinds of information for structure prediction: template and multiple sequence alignment (MSA) embedding. Templates have been used by some methods before, such as AlphaFold2, RoseTTAFold and RaptorX. AlphaFold2 and RosetTTAFold only used templates detected by HHsearch, which may not perform very well on some targets. In addition, sequence embedding generated by pre-trained protein language models has not been fully explored for structure prediction. In this article, we study the impact of templates (including the number of templates, the template quality and how the templates are generated) on protein structure prediction accuracy, especially when the templates are detected by methods other than HHsearch. We also study the impact of sequence embedding (generated by MSATransformer and ESM-1b) on structure prediction. RESULTS: We have implemented a deep learning method for protein structure prediction that may take templates and MSA embedding as extra inputs. We study the contribution of templates and MSA embedding to structure prediction accuracy. Our experimental results show that templates can improve structure prediction on 71 of 110 CASP13 (13th Critical Assessment of Structure Prediction) targets and 47 of 91 CASP14 targets, and templates are particularly useful for targets with similar templates. MSA embedding can improve structure prediction on 63 of 91 CASP14 (14th Critical Assessment of Structure Prediction) targets and 87 of 183 CAMEO targets and is particularly useful for proteins with shallow MSAs. When both templates and MSA embedding are used, our method can predict correct folds (TMscore > 0.5) for 16 of 23 CASP14 FM targets and 14 of 18 Continuous Automated Model Evaluation (CAMEO) targets, outperforming RoseTTAFold by 5% and 7%, respectively. AVAILABILITY AND IMPLEMENTATION: Available at https://github.com/xluo233/RaptorXFold. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Accurately estimating protein model quality in the absence of experimental structure is not only important for model evaluation and selection but also useful for model refinement. Progress has been steadily made by introducing new features and algorithms (especially deep neural networks), but the accuracy of quality assessment (QA) is still not very satisfactory, especially local QA on hard protein targets. RESULTS: We propose a new single-model-based QA method ResNetQA for both local and global quality assessment. Our method predicts model quality by integrating sequential and pairwise features using a deep neural network composed of both 1D and 2D convolutional residual neural networks (ResNet). The 2D ResNet module extracts useful information from pairwise features such as model-derived distance maps, co-evolution information, and predicted distance potential from sequences. The 1D ResNet is used to predict local (global) model quality from sequential features and pooled pairwise information generated by 2D ResNet. Tested on the CASP12 and CASP13 datasets, our experimental results show that our method greatly outperforms existing state-of-the-art methods. Our ablation studies indicate that the 2D ResNet module and pairwise features play an important role in improving model quality assessment. AVAILABILITY AND IMPLEMENTATION: https://github.com/AndersJing/ResNetQA. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

As the first step of machine-learning based protein structure and function prediction, the amino acid encoding play a fundamental role in the final success of those methods. Different from the protein sequence encoding, the amino acid encoding can be used in both residue-level and sequence-level prediction of protein properties by combining them with different algorithms. However, it has not attracted enough attention in the past decades, and there are no comprehensive reviews and assessments about encoding methods so far. In this article, we make a systematic classification and propose a comprehensive review and assessment for various amino acid encoding methods. Those methods are grouped into five categories according to their information sources and information extraction methodologies, including binary encoding, physicochemical properties encoding, evolution-based encoding, structure-based encoding, and machine-learning encoding. Then, 16 representative methods from five categories are selected and compared on protein secondary structure prediction and protein fold recognition tasks by using large-scale benchmark datasets. The results show that the evolution-based position-dependent encoding method PSSM achieved the best performance, and the structure-based and machine-learning encoding methods also show some potential for further application, the neural network based distributed representation of amino acids in particular may bring new light to this area. We hope that the review and assessment are useful for future studies in amino acid encoding.

BACKGROUND: Protein structure prediction has achieved a lot of progress during the last few decades and a greater number of models for a certain sequence can be predicted. Consequently, assessing the qualities of predicted protein models in perspective is one of the key components of successful protein structure prediction. Over the past years, a number of methods have been developed to address this issue, which could be roughly divided into three categories: single methods, quasi-single methods and clustering (or consensus) methods. Although these methods achieve much success at different levels, accurate protein model quality assessment is still an open problem. RESULTS: Here, we present the MQAPRank, a global protein model quality assessment program based on learning-to-rank. The MQAPRank first sorts the decoy models by using single method based on learning-to-rank algorithm to indicate their relative qualities for the target protein. And then it takes the first five models as references to predict the qualities of other models by using average GDT_TS scores between reference models and other models. Benchmarked on CASP11 and 3DRobot datasets, the MQAPRank achieved better performances than other leading protein model quality assessment methods. Recently, the MQAPRank participated in the CASP12 under the group name FDUBio and achieved the state-of-the-art performances. CONCLUSIONS: The MQAPRank provides a convenient and powerful tool for protein model quality assessment with the state-of-the-art performances, it is useful for protein structure prediction and model quality assessment usages.

BACKGROUND: In structural biology area, protein residue-residue contacts play a crucial role in protein structure prediction. Some researchers have found that the predicted residue-residue contacts could effectively constrain the conformational search space, which is significant for de novo protein structure prediction. In the last few decades, related researchers have developed various methods to predict residue-residue contacts, especially, significant performance has been achieved by using fusion methods in recent years. In this work, a novel fusion method based on rank strategy has been proposed to predict contacts. Unlike the traditional regression or classification strategies, the contact prediction task is regarded as a ranking task. First, two kinds of features are extracted from correlated mutations methods and ensemble machine-learning classifiers, and then the proposed method uses the learning-to-rank algorithm to predict contact probability of each residue pair. RESULTS: First, we perform two benchmark tests for the proposed fusion method (RRCRank) on CASP11 dataset and CASP12 dataset respectively. The test results show that the RRCRank method outperforms other well-developed methods, especially for medium and short range contacts. Second, in order to verify the superiority of ranking strategy, we predict contacts by using the traditional regression and classification strategies based on the same features as ranking strategy. Compared with these two traditional strategies, the proposed ranking strategy shows better performance for three contact types, in particular for long range contacts. Third, the proposed RRCRank has been compared with several state-of-the-art methods in CASP11 and CASP12. The results show that the RRCRank could achieve comparable prediction precisions and is better than three methods in most assessment metrics. CONCLUSIONS: The learning-to-rank algorithm is introduced to develop a novel rank-based method for the residue-residue contact prediction of proteins, which achieves state-of-the-art performance based on the extensive assessment.

Protein residue-residue contacts dictate the topology of protein structure and play an important role in structural biology, especially in de novo protein structure prediction. Accurate prediction of residue contacts could improve the performance of de novo protein structure prediction methods. In this study, a novel method based on learning-to-rank (RRCRank) has been presented to predict protein residue-residue contacts. The proposed method formulates the contacts prediction problem as a ranking problem. Firstly, the contact probabilities of residue pairs are predicted by ensemble machine-learning classifiers and correlated mutations approaches. And then, the proposed method integrates the complementary outputs of machine-learning and correlated mutations approaches and uses the learning-to-rank algorithm to rank residue pairs based on their probabilities to be contacts. Benchmarked on the CASP11 dataset, the proposed method achieves an improved performance for all three categories of contacts (short-range, medium-range and long-range contacts), which shows the proposed method based on learning-to-rank could take advantage of machine-learning and correlated mutations approaches and could provide the state-of-the-art performance.

Protein structures are essential to understand the function. The predicted models have a broad range of the accuracy. Reliable estimates of the model quality are critical in determining the usefulness of the model to address a specific problem. In this study, a novel method has been presented to rank the models by their relative qualities. The proposed method first extracts various features from the three dimensional structures of proteins and then the learning-to-rank algorithm is used to rank the models based on their similarities with the native structures. Furthermore, a quasi single-model method is presented, which uses the top five identified models as references and ranks the other models by the average similarity with the reference models. Benchmark test is performed on a newly developed, template-based decoy generators which covers all the main structure classes of proteins. The proposed learning-to-rank method achieves an average Pearson correlation coefficient of 0.94 and a AUC value of 0.97, which consistently outperform all other well-developed methods. The quasi single-model can further improves the performance and achieve nearly perfect results with both PCC and AUC value of 0.99. The results demonstrate that the proposed method is an effective methodology for model quality assessment and provides the state-of-the-art performance.