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Background The segment overlap score (SOV) has been used to evaluate the predicted protein secondary structures, a sequence composed of helix (H), strand (E), and coil (C), by comparing it with the native or reference secondary structures, another sequence of H, E, and C. SOV’s advantage is that it can consider the size of continuous overlapping segments and assign extra allowance to longer continuous overlapping segments instead of only judging from the percentage of overlapping individual positions as Q3 score does. However, we have found a drawback from its previous definition, that is, it cannot ensure increasing allowance assignment when more residues in a segment are further predicted accurately. Results A new way of assigning allowance has been designed, which keeps all the advantages of the previous SOV score definitions and ensures that the amount of allowance assigned is incremental when more elements in a segment are predicted accurately. Furthermore, our improved SOV has achieved a higher correlation with the quality of protein models measured by GDT-TS score and TM-score, indicating its better abilities to evaluate tertiary structure quality at the secondary structure level. We analyzed the statistical significance of SOV scores and found the threshold values for distinguishing two protein structures (SOV_refine  > 0.19) and indicating whether two proteins are under the same CATH fold (SOV_refine > 0.94 and > 0.90 for three- and eight-state secondary structures respectively). We provided another two example applications, which are when used as a machine learning feature for protein model quality assessment and comparing different definitions of topologically associating domains. We proved that our newly defined SOV score resulted in better performance. Conclusions The SOV score can be widely used in bioinformatics research and other fields that need to compare two sequences of letters in which continuous segments have important meanings. We also generalized the previous SOV definitions so that it can work for sequences composed of more than three states (e.g., it can work for the eight-state definition of protein secondary structures). A standalone software package has been implemented in Perl with source code released. The software can be downloaded from http://dna.cs.miami.edu/SOV/ .

Background Predicting protein function and structure from sequence is one important challenge for computational biology. For 26 years, most state-of-the-art approaches combined machine learning and evolutionary information. However, for some applications retrieving related proteins is becoming too time-consuming. Additionally, evolutionary information is less powerful for small families, e.g. for proteins from the Dark Proteome . Both these problems are addressed by the new methodology introduced here. Results We introduced a novel way to represent protein sequences as continuous vectors ( embeddings ) by using the language model ELMo taken from natural language processing. By modeling protein sequences, ELMo effectively captured the biophysical properties of the language of life from unlabeled big data (UniRef50). We refer to these new embeddings as SeqVec ( Seq uence-to- Vec tor) and demonstrate their effectiveness by training simple neural networks for two different tasks. At the per-residue level, secondary structure (Q3 = 79% ± 1, Q8 = 68% ± 1) and regions with intrinsic disorder (MCC = 0.59 ± 0.03) were predicted significantly better than through one-hot encoding or through Word2vec-like approaches. At the per-protein level, subcellular localization was predicted in ten classes (Q10 = 68% ± 1) and membrane-bound were distinguished from water-soluble proteins (Q2 = 87% ± 1). Although SeqVec embeddings generated the best predictions from single sequences, no solution improved over the best existing method using evolutionary information. Nevertheless, our approach improved over some popular methods using evolutionary information and for some proteins even did beat the best. Thus, they prove to condense the underlying principles of protein sequences. Overall, the important novelty is speed: where the lightning-fast HHblits needed on average about two minutes to generate the evolutionary information for a target protein, SeqVec created embeddings on average in 0.03 s. As this speed-up is independent of the size of growing sequence databases, SeqVec provides a highly scalable approach for the analysis of big data in proteomics, i.e. microbiome or metaproteome analysis. Conclusion Transfer-learning succeeded to extract information from unlabeled sequence databases relevant for various protein prediction tasks. SeqVec modeled the language of life, namely the principles underlying protein sequences better than any features suggested by textbooks and prediction methods. The exception is evolutionary information, however, that information is not available on the level of a single sequence.

Accurately predicting peptide secondary structures remains a challenging task due to the lack of discriminative information in short peptides. In this study, PHAT is proposed, a deep hypergraph learning framework for the prediction of peptide secondary structures and the exploration of downstream tasks. The framework includes a novel interpretable deep hypergraph multi‐head attention network that uses residue‐based reasoning for structure prediction. The algorithm can incorporate sequential semantic information from large‐scale biological corpus and structural semantic information from multi‐scale structural segmentation, leading to better accuracy and interpretability even with extremely short peptides. The interpretable models are able to highlight the reasoning of structural feature representations and the classification of secondary substructures. The importance of secondary structures in peptide tertiary structure reconstruction and downstream functional analysis is further demonstrated, highlighting the versatility of our models. To facilitate the use of the model, an online server is established which is accessible via http://inner.wei‐group.net/PHAT/. The work is expected to assist in the design of functional peptides and contribute to the advancement of structural biology research. Accurately predicting peptide secondary structures remains a challenging task due to the lack of discriminative information in short peptides. Based on transfer learning and hypergraph algorithm, sequential semantic information can be incorporated from large‐scale biological corpus and structural. semantic information from multi‐scale structural segmentation, leading to better accuracy and interpretability even with extremely short peptides.

Background Recently developed methods of protein contact prediction, a crucially important step for protein structure prediction, depend heavily on deep neural networks (DNNs) and multiple sequence alignments (MSAs) of target proteins. Protein sequences are accumulating to an increasing degree such that abundant sequences to construct an MSA of a target protein are readily obtainable. Nevertheless, many cases present different ends of the number of sequences that can be included in an MSA used for contact prediction. The abundant sequences might degrade prediction results, but opportunities remain for a limited number of sequences to construct an MSA. To resolve these persistent issues, we strove to develop a novel framework using DNNs in an end-to-end manner for contact prediction. Results We developed neural network models to improve precision of both deep and shallow MSAs. Results show that higher prediction accuracy was achieved by assigning weights to sequences in a deep MSA. Moreover, for shallow MSAs, adding a few sequential features was useful to increase the prediction accuracy of long-range contacts in our model. Based on these models, we expanded our model to a multi-task model to achieve higher accuracy by incorporating predictions of secondary structures and solvent-accessible surface areas. Moreover, we demonstrated that ensemble averaging of our models can raise accuracy. Using past CASP target protein domains, we tested our models and demonstrated that our final model is superior to or equivalent to existing meta-predictors. Conclusions The end-to-end learning framework we built can use information derived from either deep or shallow MSAs for contact prediction. Recently, an increasing number of protein sequences have become accessible, including metagenomic sequences, which might degrade contact prediction results. Under such circumstances, our model can provide a means to reduce noise automatically. According to results of tertiary structure prediction based on contacts and secondary structures predicted by our model, more accurate three-dimensional models of a target protein are obtainable than those from existing ECA methods, starting from its MSA. DeepECA is available from https://github.com/tomiilab/DeepECA .

The secondary structure of a protein serves as the foundation for constructing its three-dimensional (3D) structure, which in turn is critical for determining its function and role in biological processes. Therefore, accurately predicting secondary structure not only facilitates the understanding of a protein’s 3D conformation but also provides essential insights into its interactions, functional mechanisms, and potential applications in biomedical research. Deep learning models are particularly effective in protein secondary structure prediction because of their ability to process complex sequence data and extract meaningful patterns, thereby increasing prediction accuracy and efficiency. This study proposes a combined model, ITBM-KD, which integrates an improved temporal convolutional network (TCN), bidirectional recurrent neural network (BiRNN), and multilayer perceptron (MLP) to increase the accuracy of protein secondary structure prediction for octapeptides and tripeptides. By combining one-hot encoding, word vector representation of physicochemical properties, and knowledge distillation with the ProtT5 model, the proposed model achieves excellent performance on multiple datasets. To evaluate its effectiveness, two classic datasets, TS115 and CB513, containing 115 and 513 protein datasets, respectively, were used. In addition, 15,078 protein data points collected from the PDB database from June 6, 2018, to June 6, 2020, were used to further verify the robustness and generalizability of the model. This study improves prediction accuracy and provides an essential model for understanding protein structure and function, especially in resource-limited settings.

Protein structure prediction continues to pose multiple challenges despite outstanding progress that is largely attributable to the use of novel machine learning techniques. One of the widely used representations of local 3D structure—protein blocks (PBs)—can be treated in a similar way to secondary structure classes. Here, we present a new approach for predicting local conformation in terms of PB classes solely from amino acid sequences. We apply the RMSD metric to ensure unambiguous future 3D protein structure recovery. The selection of statistically assessed features is a key component of the proposed method. We suggest that ML input features should be created from the statistically significant predictors that are derived from the amino acids’ physicochemical properties and the resolved structures’ statistics. The statistical significance of the suggested features was assessed using a stepwise regression analysis that permitted the evaluation of the contribution and statistical significance of each predictor. We used the set of 380 statistically significant predictors as a learning model for the regression neural network that was trained using the PISCES30 dataset. When using the same dataset and metrics for benchmarking, our method outperformed all other methods reported in the literature for the CB513 nonredundant dataset (for the PBs, Q16 = 81.01%, and for the DSSP, Q3 = 85.99% and Q8 = 79.35%).

Background The prediction of protein secondary structures is a crucial and significant step for ab initio tertiary structure prediction which delivers the information about proteins activity and functions. As the experimental methods are expensive and sometimes impossible, many SS predictors, mainly based on different machine learning methods have been proposed for many years. Currently, most of the top methods use evolutionary-based input features produced by PSSM and HHblits software, although quite recently the embeddings—the new description of protein sequences generated by language models (LM) have appeared that could be leveraged as input features. Apart from input features calculation, the top models usually need extensive computational resources for training and prediction and are barely possible to run on a regular PC. SS prediction as the imbalanced classification problem should not be judged by the commonly used Q3/Q8 metrics. Moreover, as the benchmark datasets are not random samples, the classical statistical null hypothesis testing based on the Neyman–Pearson approach is not appropriate. Results We present a lightweight deep network ProteinUnet2 for SS prediction which is based on U-Net convolutional architecture and evolutionary-based input features (from PSSM and HHblits) as well as SPOT-Contact features. Through an extensive evaluation study, we report the performance of ProteinUnet2 in comparison with top SS prediction methods based on evolutionary information (SAINT and SPOT-1D). We also propose a new statistical methodology for prediction performance assessment based on the significance from Fisher–Pitman permutation tests accompanied by practical significance measured by Cohen’s effect size. Conclusions Our results suggest that ProteinUnet2 architecture has much shorter training and inference times while maintaining results similar to SAINT and SPOT-1D predictors. Taking into account the relatively long times of calculating evolutionary-based features (from PSSM in particular), it would be worth conducting the predictive ability tests on embeddings as input features in the future. We strongly believe that our proposed here statistical methodology for the evaluation of SS prediction results will be adopted and used (and even expanded) by the research community.

Protein structure prediction continues to pose multiple challenges, despite the progress made by ML. While recent deep learning models have achieved a strong performance using embeddings from protein language models, they often ignore non-canonical amino acids and rely heavily on sequence alignments or evolutionary profiles. Here, we present an improvement to this approach for predicting the secondary protein structure of DSSP classes solely from amino acid sequences. We suggest that ML feature sets should be generated from statistically significant mutually uncorrelated descriptors. The selection of statistically assessed descriptors, including predicting the physicochemical parameters of non-canonical amino acids, is a key component of the proposed method. The statistical significance and influence of each of the suggested features were assessed using a two-step Linear Discriminant Analysis, which permitted the evaluation of the statistical significance of each descriptor and their impact on model accuracy. We applied the set of 109 most influential statistically significant descriptors as a learning model for the two-layer Bi-LSTM network combined with ESMFold2 embeddings. Our method, TruMPET (Training upon Multiple Pre-selected Elements Technique), outperformed all other methods reported in the literature for the non-redundant datasets (CB513: DSSP Q3 = 91.36% and Q8 = 85.41%, TEST2018: DSSP Q3 = 90.64% and Q8 = 84.17%).

The active functionalities of RNA are recognized to be heavily dependent on the structure and sequence. Therefore, a model that can accurately evaluate a design by giving RNA sequence-structure pairs would be a valuable tool for many researchers. Machine learning methods have been explored to develop such tools, showing promising results. However, two key issues remain. Firstly, the performance of machine learning models is affected by the features used to characterize RNA. Currently, there is no consensus on which features are the most effective for characterizing RNA sequence-structure pairs. Secondly, most existing machine learning methods extract features describing entire RNA molecule. We argue that it is essential to define additional features that characterize nucleotides and specific sections of RNA structure to enhance the overall efficacy of the RNA design process. We develop two deep learning models for evaluating RNA sequence-secondary structure pairs. The first model, NU-ResNet, uses a convolutional neural network architecture that solves the aforementioned problems by explicitly encoding RNA sequence-structure information into a 3D matrix. Building upon NU-ResNet, our second model, NUMO-ResNet, incorporates additional information derived from the characterizations of RNA, specifically the 2D folding motifs. In this work, we introduce an automated method to extract these motifs based on fundamental secondary structure descriptions. We evaluate the performance of both models on an independent testing dataset. Our proposed models outperform the models from literatures in this independent testing dataset. To assess the robustness of our models, we conduct 10-fold cross validation. To evaluate the generalization ability of NU-ResNet and NUMO-ResNet across different RNA families, we train and test our proposed models in different RNA families. Our proposed models show superior performance compared to the models from literatures when being tested across different independent RNA families. In this study, we propose two deep learning models, NU-ResNet and NUMO-ResNet, to evaluate RNA sequence-secondary structure pairs. These two models expand the field of data-driven approaches for learning RNA. Furthermore, these two models provide the new method to encode RNA sequence-secondary structure pairs.

Protein secondary structure provides rich structural information, hence the description and understanding of protein structure relies heavily on it. Identification or prediction of secondary structures therefore plays an important role in protein research. In protein NMR studies, it is more convenient to predict secondary structures from chemical shifts as compared to the traditional determination methods based on inter-nuclear distances provided by NOESY experiment. In recent years, there was a significant improvement observed in deep neural networks, which had been applied in many research fields. Here we proposed a deep neural network based on bidirectional long short term memory (biLSTM) to predict protein 3-state secondary structure using NMR chemical shifts of backbone nuclei. While comparing with the existing methods the proposed method showed better prediction accuracy. Based on the proposed method, a web server has been built to provide protein secondary structure prediction service.