Combining pairwise structural similarity and deep learning interface contact prediction to estimate protein complex model accuracy in CASP15.

Estimating the accuracy of quaternary structural models of protein complexes and assemblies (EMA) is important for predicting quaternary structures and applying them to studying protein function and interaction. The pairwise similarity between structural models is proven useful for estimating the quality of protein tertiary structural models, but it has been rarely applied to predicting the quality of quaternary structural models. Moreover, the pairwise similarity approach often fails when many structural models are of low quality and similar to each other. To address the gap, we developed a hybrid method (MULTICOM_qa) combining a pairwise similarity score (PSS) and an interface contact probability score (ICPS) based on the deep learning inter-chain contact prediction for estimating protein complex model accuracy. It blindly participated in the 15th Critical Assessment of Techniques for Protein Structure Prediction (CASP15) in 2022 and performed very well in estimating the global structure accuracy of assembly models. The average per-target correlation coefficient between the model quality scores predicted by MULTICOM_qa and the true quality scores of the models of CASP15 assembly targets is 0.66. The average per-target ranking loss in using the predicted quality scores to rank the models is 0.14. It was able to select good models for most targets. Moreover, several key factors (i.e., target difficulty, model sampling difficulty, skewness of model quality, and similarity between good/bad models) for EMA are identified and analyzed. The results demonstrate that combining the multi-model method (PSS) with the complementary single-model method (ICPS) is a promising approach to EMA.

Predicting residue-specific qualities of individual protein models using residual neural networks and graph neural networks.

The estimation of protein model accuracy (EMA) or model quality assessment (QA) is important for protein structure prediction. An accurate EMA algorithm can guide the refinement of models or pick the best model or best parts of models from a pool of predicted tertiary structures. We developed two novel methods: MASS2 and LAW, for predicting residue-specific or local qualities of individual models, which incorporate residual neural networks and graph neural networks, respectively. These two methods use similar features extracted from protein models but different architectures of neural networks to predict the local accuracies of single models. MASS2 and LAW participated in the QA category of CASP14, and according to our evaluations based on CASP14 official criteria, MASS2 and LAW are the best and second-best methods based on the Z-scores of ASE/100, AUC, and ULR-1.F1. We also evaluated MASS2, LAW, and the residue-specific predicted deviations (between model and native structure) generated by AlphaFold2 on CASP14 AlphaFold2 tertiary structure (TS) models. LAW achieved comparable or better performances compared to the predicted deviations generated by AlphaFold2 on AlphaFold2 TS models, even though LAW was not trained on any AlphaFold2 TS models. Specifically, LAW performed better on AUC and ULR scores, and AlphaFold2 performed better on ASE scores. This means that AlphaFold2 is better at predicting deviations, but LAW is better at classifying accurate and inaccurate residues and detecting unreliable local regions. MASS2 and LAW can be freely accessed from http://dna.cs.miami.edu/MASS2-CASP14/ and http://dna.cs.miami.edu/LAW-CASP14/, respectively.

Assessment of protein model structure accuracy estimation in CASP14: Old and new challenges.

In CASP, blind testing of model accuracy estimation methods has been conducted on models submitted by tertiary structure prediction servers. In CASP14, model accuracy estimation results were evaluated in terms of both global and local structure accuracy, as in the previous CASPs. Unlike the previous CASPs that did not show pronounced improvements in performance, the best single-model method (from the Baker group) showed an improved performance in CASP14, particularly in evaluating global structure accuracy when compared to both the best single-model methods in previous CASPs and the best multi-model methods in the current CASP. Although the CASP14 experiment on model accuracy estimation did not deal with the structures generated by AlphaFold2, new challenges that have arisen due to the success of AlphaFold2 are discussed.

MASS: predict the global qualities of individual protein models using random forests and novel statistical potentials.

BACKGROUND: Protein model quality assessment (QA) is an essential procedure in protein structure prediction. QA methods can predict the qualities of protein models and identify good models from decoys. Clustering-based methods need a certain number of models as input. However, if a pool of models are not available, methods that only need a single model as input are indispensable. RESULTS: We developed MASS, a QA method to predict the global qualities of individual protein models using random forests and various novel energy functions. We designed six novel energy functions or statistical potentials that can capture the structural characteristics of a protein model, which can also be used in other protein-related bioinformatics research. MASS potentials demonstrated higher importance than the energy functions of RWplus, GOAP, DFIRE and Rosetta when the scores they generated are used as machine learning features. MASS outperforms almost all of the four CASP11 top-performing single-model methods for global quality assessment in terms of all of the four evaluation criteria officially used by CASP, which measure the abilities to assign relative and absolute scores, identify the best model from decoys, and distinguish between good and bad models. MASS has also achieved comparable performances with the leading QA methods in CASP12 and CASP13. CONCLUSIONS: MASS and the source code for all MASS potentials are publicly available at http://dna.cs.miami.edu/MASS/ .

A single-model quality assessment method for poor quality protein structure.

BACKGROUND: Quality assessment of protein tertiary structure prediction models, in which structures of the best quality are selected from decoys, is a major challenge in protein structure prediction, and is crucial to determine a model's utility and potential applications. Estimating the quality of a single model predicts the model's quality based on the single model itself. In general, the Pearson correlation value of the quality assessment method increases in tandem with an increase in the quality of the model pool. However, there is no consensus regarding the best method to select a few good models from the poor quality model pool. RESULTS: We introduce a novel single-model quality assessment method for poor quality models that uses simple linear combinations of six features. We perform weighted search and linear regression on a large dataset of models from the 12th Critical Assessment of Protein Structure Prediction (CASP12) and benchmark the results on CASP13 models. We demonstrate that our method achieves outstanding performance on poor quality models. CONCLUSIONS: According to results of poor protein structure assessment based on six features, contact prediction and relying on fewer prediction features can improve selection accuracy.

Assessment of protein model structure accuracy estimation in CASP13: Challenges in the era of deep learning.

Scoring model structure is an essential component of protein structure prediction that can affect the prediction accuracy tremendously. Users of protein structure prediction results also need to score models to select the best models for their application studies. In Critical Assessment of techniques for protein Structure Prediction (CASP), model accuracy estimation methods have been tested in a blind fashion by providing models submitted by the tertiary structure prediction servers for scoring. In CASP13, model accuracy estimation results were evaluated in terms of both global and local structure accuracy. Global structure accuracy estimation was evaluated by the quality of the models selected by the global structure scores and by the absolute estimates of the global scores. Residue-wise, local structure accuracy estimations were evaluated by three different measures. A new measure introduced in CASP13 evaluates the ability to predict inaccurately modeled regions that may be improved by refinement. An intensive comparative analysis on CASP13 and the previous CASPs revealed that the tertiary structure models generated by the CASP13 servers show very distinct features. Higher consensus toward models of higher global accuracy appeared even for free modeling targets, and many models of high global accuracy were not well optimized at the atomic level. This is related to the new technology in CASP13, deep learning for tertiary contact prediction. The tertiary model structures generated by deep learning pose a new challenge for EMA (estimation of model accuracy) method developers. Model accuracy estimation itself is also an area where deep learning can potentially have an impact, although current EMA methods have not fully explored that direction.

Protein tertiary structure modeling driven by deep learning and contact distance prediction in CASP13.

Predicting residue-residue distance relationships (eg, contacts) has become the key direction to advance protein structure prediction since 2014 CASP11 experiment, while deep learning has revolutionized the technology for contact and distance distribution prediction since its debut in 2012 CASP10 experiment. During 2018 CASP13 experiment, we enhanced our MULTICOM protein structure prediction system with three major components: contact distance prediction based on deep convolutional neural networks, distance-driven template-free (ab initio) modeling, and protein model ranking empowered by deep learning and contact prediction. Our experiment demonstrates that contact distance prediction and deep learning methods are the key reasons that MULTICOM was ranked 3rd out of all 98 predictors in both template-free and template-based structure modeling in CASP13. Deep convolutional neural network can utilize global information in pairwise residue-residue features such as coevolution scores to substantially improve contact distance prediction, which played a decisive role in correctly folding some free modeling and hard template-based modeling targets. Deep learning also successfully integrated one-dimensional structural features, two-dimensional contact information, and three-dimensional structural quality scores to improve protein model quality assessment, where the contact prediction was demonstrated to consistently enhance ranking of protein models for the first time. The success of MULTICOM system clearly shows that protein contact distance prediction and model selection driven by deep learning holds the key of solving protein structure prediction problem. However, there are still challenges in accurately predicting protein contact distance when there are few homologous sequences, folding proteins from noisy contact distances, and ranking models of hard targets.

MQAPRank: improved global protein model quality assessment by learning-to-rank.

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.

DeepQA: improving the estimation of single protein model quality with deep belief networks.

BACKGROUND: Protein quality assessment (QA) useful for ranking and selecting protein models has long been viewed as one of the major challenges for protein tertiary structure prediction. Especially, estimating the quality of a single protein model, which is important for selecting a few good models out of a large model pool consisting of mostly low-quality models, is still a largely unsolved problem. RESULTS: We introduce a novel single-model quality assessment method DeepQA based on deep belief network that utilizes a number of selected features describing the quality of a model from different perspectives, such as energy, physio-chemical characteristics, and structural information. The deep belief network is trained on several large datasets consisting of models from the Critical Assessment of Protein Structure Prediction (CASP) experiments, several publicly available datasets, and models generated by our in-house ab initio method. Our experiments demonstrate that deep belief network has better performance compared to Support Vector Machines and Neural Networks on the protein model quality assessment problem, and our method DeepQA achieves the state-of-the-art performance on CASP11 dataset. It also outperformed two well-established methods in selecting good outlier models from a large set of models of mostly low quality generated by ab initio modeling methods. CONCLUSION: DeepQA is a useful deep learning tool for protein single model quality assessment and protein structure prediction. The source code, executable, document and training/test datasets of DeepQA for Linux is freely available to non-commercial users at http://cactus.rnet.missouri.edu/DeepQA/ .

Assessment of the Performances of the Protein Modeling Techniques Participating in CASP15 Using a Structure-Based Functional Site Prediction Approach: ResiRole.

BACKGROUND: Model quality assessments via computational methods which entail comparisons of the modeled structures to the experimentally determined structures are essential in the field of protein structure prediction. The assessments provide means to benchmark the accuracies of the modeling techniques and to aid with their development. We previously described the ResiRole method to gauge model quality principally based on the preservation of the structural characteristics described in SeqFEATURE functional site prediction models. METHODS: We apply ResiRole to benchmark modeling group performances in the Critical Assessment of Structure Prediction experiment, round 15. To gauge model quality, a normalized Predicted Functional site Similarity Score (PFSS) was calculated as the average of one minus the absolute values of the differences of the functional site prediction probabilities, as found for the experimental structures versus those found at the corresponding sites in the structure models. RESULTS: The average PFSS per modeling group (gPFSS) correlates with standard quality metrics, and can effectively be used to rank the accuracies of the groups. For the free modeling (FM) category, correlation coefficients of the Local Distance Difference Test (LDDT) and Global Distance Test-Total Score (GDT-TS) metrics with gPFSS were 0.98239 and 0.87691, respectively. An example finding for a specific group is that the gPFSS for EMBER3D was higher than expected based on the predictive relationship between gPFSS and LDDT. We infer the result is due to the use of constraints imprinted by function that are a part of the EMBER3D methodology. Also, we find functional site predictions that may guide further functional characterizations of the respective proteins. CONCLUSION: The gPFSS metric provides an effective means to assess and rank the performances of the structure prediction techniques according to their abilities to accurately recount the structural features at predicted functional sites.

Assembled graph neural network using graph transformer with edges for protein model quality assessment.

Acquainting protein's structure is of vital importance to accurately understanding its function. Computational method of deep learning has made great progress in protein structure prediction from sequence, and has the potential to help structural biology research. The computational methods usually require independent protein structure model quality assessment to select the best from the model pool or guide protein structure refinement. We construct a graph neural network finely assembled with Graph Transformer Feature Extractor and message-passing layers for protein model quality assessment. The graph based method can more naturally embody the protein structure than a sequence or voxelized representation method. Although the widely used graph convolutional network has a strong ability to learn spatial patterns, it does not weigh the dependencies of different nodes on other nodes. So we introduce Graph Transformer to excavate the different degrees of neighboring residue nodes contributing to their local environments and extract local features. This is subsequently followed by message-passing layers to transmit-receive local information. Our network makes better use of edge information and is lightweight since relatively few input features and number of network layers, and experimental results demonstrate that our model outperforms various existing methods. Core code is made freely available at: https://github.com/Crystal-Dsq/proteinqa.

MUfoldQA_G: High-accuracy protein model QA via retraining and transformation.

Protein tertiary structure prediction is an active research area and has attracted significant attention recently due to the success of AlphaFold from DeepMind. Methods capable of accurately evaluating the quality of predicted models are of great importance. In the past, although many model quality assessment (QA) methods have been developed, their accuracies are not consistently high across different QA performance metrics for diverse target proteins. In this paper, we propose MUfoldQA_G, a new multi-model QA method that aims at simultaneously optimizing Pearson correlation and average GDT-TS difference, two commonly used QA performance metrics. This method is based on two new algorithms MUfoldQA_Gp and MUfoldQA_Gr. MUfoldQA_Gp uses a new technique to combine information from protein templates and reference protein models to maximize the Pearson correlation QA metric. MUfoldQA_Gr employs a new machine learning technique that resamples training data and retrains adaptively to learn a consensus model that is better than naïve consensus while minimizing average GDT-TS difference. MUfoldQA_G uses a new method to combine the results of MUfoldQA_Gr and MUfoldQA_Gp so that the final QA prediction results achieve low average GDT-TS difference that is close to the results from MUfoldQA_Gr, while maintaining high Pearson correlation that is the same as the results from MUfoldQA_Gp. In CASP14 QA categories, MUfoldQA_G ranked No. 1 in Pearson correlation and No. 2 in average GDT-TS difference.

Estimating local protein model quality: prospects for molecular replacement.

Model quality assessment programs estimate the quality of protein models and can be used to estimate local error in protein models. ProQ3D is the most recent and most accurate version of our software. Here, it is demonstrated that it is possible to use local error estimates to substantially increase the quality of the models for molecular replacement (MR). Adjusting the B factors using ProQ3D improved the log-likelihood gain (LLG) score by over 50% on average, resulting in significantly more successful models in MR compared with not using error estimates. On a data set of 431 homology models to address difficult MR targets, models with error estimates from ProQ3D received an LLG of >50 for almost half of the models 209/431 (48.5%), compared with 175/431 (40.6%) for the previous version, ProQ2, and only 74/431 (17.2%) for models with no error estimates, clearly demonstrating the added value of using error estimates to enable MR for more targets. ProQ3D is available from http://proq3.bioinfo.se/ both as a server and as a standalone download.

DL-PRO: A Novel Deep Learning Method for Protein Model Quality Assessment.

Computational protein structure prediction is very important for many applications in bioinformatics. In the process of predicting protein structures, it is essential to accurately assess the quality of generated models. Although many single-model quality assessment (QA) methods have been developed, their accuracy is not high enough for most real applications. In this paper, a new approach based on C-α atoms distance matrix and machine learning methods is proposed for single-model QA and the identification of native-like models. Different from existing energy/scoring functions and consensus approaches, this new approach is purely geometry based. Furthermore, a novel algorithm based on deep learning techniques, called DL-Pro, is proposed. For a protein model, DL-Pro uses its distance matrix that contains pairwise distances between two residues' C-α atoms in the model, which sometimes is also called contact map, as an orientation-independent representation. From training examples of distance matrices corresponding to good and bad models, DL-Pro learns a stacked autoencoder network as a classifier. In experiments on selected targets from the Critical Assessment of Structure Prediction (CASP) competition, DL-Pro obtained promising results, outperforming state-of-the-art energy/scoring functions, including OPUS-CA, DOPE, DFIRE, and RW.