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The regulatory and effector functions of T cells are initiated by the binding of their cell-surface T cell receptor (TCR) to peptides presented by major histocompatibility complex (MHC) proteins on other cells. The specificity of TCR:peptide-MHC interactions, thus, underlies nearly all adaptive immune responses. Despite intense interest, generalizable predictive models of TCR:peptide-MHC specificity remain out of reach; two key barriers are the diversity of TCR recognition modes and the paucity of training data. Inspired by recent breakthroughs in protein structure prediction achieved by deep neural networks, we evaluated structural modeling as a potential avenue for prediction of TCR epitope specificity. We show that a specialized version of the neural network predictor AlphaFold can generate models of TCR:peptide-MHC interactions that can be used to discriminate correct from incorrect peptide epitopes with substantial accuracy. Although much work remains to be done for these predictions to have widespread practical utility, we are optimistic that deep learning-based structural modeling represents a path to generalizable prediction of TCR:peptide-MHC interaction specificity.

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 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 prediction of three-dimensional (3D) protein structure from amino acid sequences has stood as a significant challenge in computational and structural bioinformatics for decades. Recently, the widespread integration of artificial intelligence (AI) algorithms has substantially expedited advancements in protein structure prediction, yielding numerous significant milestones. In particular, the end-to-end deep learning method AlphaFold2 has facilitated the rise of structure prediction performance to new heights, regularly competitive with experimental structures in the 14th Critical Assessment of Protein Structure Prediction (CASP14). To provide a comprehensive understanding and guide future research in the field of protein structure prediction for researchers, this review describes various methodologies, assessments, and databases in protein structure prediction, including traditionally used protein structure prediction methods, such as template-based modeling (TBM) and template-free modeling (FM) approaches; recently developed deep learning-based methods, such as contact/distance-guided methods, end-to-end folding methods, and protein language model (PLM)-based methods; multi-domain protein structure prediction methods; the CASP experiments and related assessments; and the recently released AlphaFold Protein Structure Database (AlphaFold DB). We discuss their advantages, disadvantages, and application scopes, aiming to provide researchers with insights through which to understand the limitations, contexts, and effective selections of protein structure prediction methods in protein-related fields.

The refinement of predicted 3D protein models is crucial in bringing them closer towards experimental accuracy for further computational studies. Refinement approaches can be divided into two main stages: The sampling and scoring stages. Sampling strategies, such as the popular Molecular Dynamics (MD)-based protocols, aim to generate improved 3D models. However, generating 3D models that are closer to the native structure than the initial model remains challenging, as structural deviations from the native basin can be encountered due to force-field inaccuracies. Therefore, different restraint strategies have been applied in order to avoid deviations away from the native structure. For example, the accurate prediction of local errors and/or contacts in the initial models can be used to guide restraints. MD-based protocols, using physics-based force fields and smart restraints, have made significant progress towards a more consistent refinement of 3D models. The scoring stage, including energy functions and Model Quality Assessment Programs (MQAPs) are also used to discriminate near-native conformations from non-native conformations. Nevertheless, there are often very small differences among generated 3D models in refinement pipelines, which makes model discrimination and selection problematic. For this reason, the identification of the most native-like conformations remains a major challenge.

AlphaFold and similar groundbreaking, AI‐based tools, have revolutionized the field of structural bioinformatics, with their remarkable accuracy in ab‐initio protein structure prediction. This success has catalyzed the development of new software and pipelines aimed at incorporating AlphaFold's predictions, often focusing on addressing the algorithm's remaining challenges. Here, we present the current landscape of structural bioinformatics shaped by AlphaFold, and discuss how the field is dynamically responding to this revolution, with new software, methods, and pipelines. While the excitement around AI‐based tools led to their widespread application, it is essential to acknowledge that their practical success hinges on their integration into established protocols within structural bioinformatics, often neglected in the context of AI‐driven advancements. Indeed, user‐driven intervention is still as pivotal in the structure prediction process as in complementing state‐of‐the‐art algorithms with functional and biological knowledge. Rendering of a GFP‐like fluorescent protein, starting from its AF‐generated PDB coordinates. Like AI algorithms for image generation focus on creating realistic and detailed content, AI‐based algorithms for protein structure generation aim to accurately generate/predict complex molecular arrangements. Figure generated using CGDream (https://cgdream.ai).

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 represents a significant challenge in the field of bioinformatics, with the prediction of protein structures using backbone dihedral angles recently achieving significant progress due to the rise of deep neural network research. However, there is a trend in protein structure prediction research to employ increasingly complex neural networks and contributions from multiple models. This study, on the other hand, explores how a single model transparently behaves using sequence data only and what can be expected from the predicted angles. To this end, the current paper presents data acquisition, deep learning model definition, and training toward the final protein backbone angle prediction. The method applies a simple fully connected neural network (FCNN) model that takes only the primary structure of the protein with a sliding window of size 21 as input to predict protein backbone ϕ and ψ dihedral angles. Despite its simplicity, the model shows surprising accuracy for the ϕ angle prediction and somewhat lower accuracy for the ψ angle prediction. Moreover, this study demonstrates that protein secondary structure prediction is also possible with simple neural networks that take in only the protein amino-acid residue sequence, but more complex models are required for higher accuracies.

Although various higher-order protein structure prediction methods have been developed, almost all of them were developed based on the three-dimensional (3D) structure information of known proteins. Here we predicted the short protein structures by molecular dynamics (MD) simulations in which only Newton’s equations of motion were used and 3D structural information of known proteins was not required. To evaluate the ability of MD simulationto predict protein structures, we calculated seven short test protein (10–46 residues) in the denatured state and compared their predicted and experimental structures. The predicted structure for Trp-cage (20 residues) was close to the experimental structure by 200-ns MD simulation. For proteins shorter or longer than Trp-cage, root-mean square deviation values were larger than those for Trp-cage. However, secondary structures could be reproduced by MD simulations for proteins with 10–34 residues. Simulations by replica exchange MD were performed, but the results were similar to those from normal MD simulations. These results suggest that normal MD simulations can roughly predict short protein structures and 200-ns simulations are frequently sufficient for estimating the secondary structures of protein (approximately 20 residues). Structural prediction method using only fundamental physical laws are useful for investigating non-natural proteins, such as primitive proteins and artificial proteins for peptide-based drug delivery systems.

Background Accurate prediction of protein tertiary structures is highly desired as the knowledge of protein structures provides invaluable insights into protein functions. We have designed two approaches to protein structure prediction, including a template-based modeling approach (called ProALIGN) and an ab initio prediction approach (called ProFOLD). Briefly speaking, ProALIGN aligns a target protein with templates through exploiting the patterns of context-specific alignment motifs and then builds the final structure with reference to the homologous templates. In contrast, ProFOLD uses an end-to-end neural network to estimate inter-residue distances of target proteins and builds structures that satisfy these distance constraints. These two approaches emphasize different characteristics of target proteins: ProALIGN exploits structure information of homologous templates of target proteins while ProFOLD exploits the co-evolutionary information carried by homologous protein sequences. Recent progress has shown that the combination of template-based modeling and ab initio approaches is promising. Results In the study, we present FALCON2, a web server that integrates ProALIGN and ProFOLD to provide high-quality protein structure prediction service. For a target protein, FALCON2 executes ProALIGN and ProFOLD simultaneously to predict possible structures and selects the most likely one as the final prediction result. We evaluated FALCON2 on widely-used benchmarks, including 104 CASP13 (the 13th Critical Assessment of protein Structure Prediction) targets and 91 CASP14 targets. In-depth examination suggests that when high-quality templates are available, ProALIGN is superior to ProFOLD and in other cases, ProFOLD shows better performance. By integrating these two approaches with different emphasis, FALCON2 server outperforms the two individual approaches and also achieves state-of-the-art performance compared with existing approaches. Conclusions By integrating template-based modeling and ab initio approaches, FALCON2 provides an easy-to-use and high-quality protein structure prediction service for the community and we expect it to enable insights into a deep understanding of protein functions.