Machine Learning Methods for Computational Proteomics and Beyond

Protein structure prediction is one of the most important problems in modern computational biology. Protein secondary structure prediction is a key step in prediction of protein tertiary structure. There have emerged many methods based on machine learning techniques, such as neural networks (NN) and support vector machine (SVM) etc., to focus on the prediction of the secondary structures. In this paper, a new method was proposed based on SVM. Different from the existing methods, this method takes into account of the physical-chemical properties and structure properties of amino acids. When tested on the most popular dataset CB513, it achieved a Q(3) accuracy of 0.7844, which illustrates that it is one of the top range methods for protein of secondary structure prediction.

Synchrotron-radiation vacuum-ultraviolet circular dichroism (VUVCD) spectroscopy can significantly improve the predictive accuracy of the contents and segment numbers of protein secondary structures by extending the short-wavelength limit of the spectra. In the present study, we combined VUVCD spectra down to 160 nm with neural-network (NN) method to improve the sequence-based prediction of protein secondary structures. The secondary structures of 30 target proteins (test set) were assigned into alpha-helices, beta-strands, and others by the DSSP program based on their X-ray crystal structures. Combining the alpha-helix and beta-strand contents estimated from the VUVCD spectra of the target proteins improved the overall sequence-based predictive accuracy Q(3) for three secondary-structure components from 59.5 to 60.7%. Incorporating the position-specific scoring matrix in the NN method improved the predictive accuracy from 70.9 to 72.1% when combining the secondary-structure contents, to 72.5% when combining the numbers of segments, and finally to 74.9% when filtering the VUVCD data. Improvement in the sequence-based prediction of secondary structures was also apparent in two other indices of the overall performance: the correlation coefficient (C) and the segment overlap value (SOV). These results suggest that VUVCD data could enhance the predictive accuracy to over 80% when combined with the currently best sequence-prediction algorithms, greatly expanding the applicability of VUVCD spectroscopy to protein structural biology.

BackgroundProtein solvent accessibility prediction is a pivotal intermediate step towards modeling protein tertiary structures directly from one-dimensional sequences. It also plays an important part in identifying protein folds and domains. Although some methods have been presented to the protein solvent accessibility prediction in recent years, the performance is far from satisfactory. In this work, we propose PredRSA, a computational method that can accurately predict relative solvent accessible surface area (RSA) of residues by exploring various local and global sequence features which have been observed to be associated with solvent accessibility. Based on these features, a novel and efficient approach, Gradient Boosted Regression Trees (GBRT), is first adopted to predict RSA.ResultsExperimental results obtained from 5-fold cross-validation based on the Manesh-215 dataset show that the mean absolute error (MAE) and the Pearson correlation coefficient (PCC) of PredRSA are 9.0 % and 0.75, respectively, which are better than that of the existing methods. Moreover, we evaluate the performance of PredRSA using an independent test set of 68 proteins. Compared with the state-of-the-art approaches (SPINE-X and ASAquick), PredRSA achieves a significant improvement on the prediction quality.ConclusionsOur experimental results show that the Gradient Boosted Regression Trees algorithm and the novel feature combination are quite effective in relative solvent accessibility prediction. The proposed PredRSA method could be useful in assisting the prediction of protein structures by applying the predicted RSA as useful restraints.

Sequence-based prediction of one dimensional structural properties of proteins has been a long-standing subproblem of protein structure prediction. Recently, prediction accuracy has been significantly improved due to the rapid expansion of protein sequence and structure libraries and advances in deep learning techniques, such as residual convolutional networks (ResNets) and Long-Short-Term Memory Cells in Bidirectional Recurrent Neural Networks (LSTM-BRNNs). Here we leverage an ensemble of LSTM-BRNN and ResNet models, together with predicted residue-residue contact maps, to continue the push towards the attainable limit of prediction for 3- and 8-state secondary structure, backbone angles (θ, τ, ϕ and ψ), half-sphere exposure, contact numbers and solvent accessible surface area (ASA). The new method, named SPOT-1D, achieves similar, high performance on a large validation set and test set (≈1000 proteins in each set), suggesting robust performance for unseen data. For the large test set, it achieves 87% and 77% in 3- and 8-state secondary structure prediction and 0.82 and 0.86 in correlation coefficients between predicted and measured ASA and contact numbers, respectively. Comparison to current state-of-the-art techniques reveals substantial improvement in secondary structure and backbone angle prediction. In particular, 44% of 40-residue fragment structures constructed from predicted backbone Cα-based θ and τ angles are less than 6 Å root-mean-squared-distance from their native conformations, nearly 20% better than the next best. The method is expected to be useful for advancing protein structure and function prediction. SPOT-1D and its data is available at: http://sparks-lab.org/. Supplementary data are available at Bioinformatics online.

The purpose of this proposes an improved prediction of protein secondary structures based on a multi-mold integrated neural network. A structure of modified artificial neural network based on built a 5-child network integrated multi-mold neural networks in which a child for each network using neural network classification is divided into two-level network is presented. Prediction comprehensive result of protein secondary structure from 5 networks is got. Profile of evolutionary information for protein sequences encoded is taken as an input of a level network. Protein sequences code is added sequence information and prediction of protein is refined by the secondary level network. It is shown that high prediction accuracy of protein secondary structure can be got by an improved multi-mold integrated neural network at 73.1%.

Combining Prediction of Protein Aggregation Propensities with Prediction of Other One-Dimensional Properties

Protein secondary structure predictions and amino acid long range contact map predictions from primary sequence of proteins have been explored to aid in modelling protein tertiary structures. In order to evaluate the usefulness of secondary structure and 3D-residue contact prediction methods to model protein structures we have used the known Q3 (alpha-helix,beta-strands and irregular turns/loops) secondary structure information, along with residue-residue contact information as restraints for MODELLER. We present here results of our modelling studies on 30 best resolved single domain protein structures of varied lengths. The results shows that it is very difficult to obtain useful models even with 100% accurate secondary structure predictions and accurate residue contact predictions for up to 30% of residues in a sequence. The best models that we obtained for proteins of lengths 37, 70, 118, 136 and 193 amino acid residues are of RMSDs 4.17, 5.27, 9.12, 7.89 and 9.69,respectively. The results show that one can obtain better models for the proteins which have high percent of alpha-helix content. This analysis further shows that MODELLER restrain optimization program can be useful only if we have truly homologous structure(s) as a template where it derives numerous restraints, almost identical to the templates used. This analysis also clearly indicates that even if we satisfy several true residue-residue contact distances, up to 30%of their sequence length with fully known secondary structural information, we end up predicting model structures much distant from their corresponding native structures.

Three-dimensional protein structure prediction is one of the major challenges in bioinformatics. According to recent research findings, real-valued distance prediction plays a vital role in determining the unique three-dimensional protein structure. This paper proposes a novel methodology involving a deep residual dense network (DRDN) for predicting protein real-valued distance. The features extracted from the given query protein sequence and its corresponding homologous sequences are used for training the model. Multi-aligned homologous sequences for each query protein sequence are retrieved from five different databases using DeepMSA, HHblits, and HITS_PR_HHblits methods. The proposed method yielded outcomes of 3.89, 0.23, 0.45, and 0.63, respectively, corresponding to the evaluation metrics such as Absolute Error, Relative Error, High-accuracy Pairwise Distance Test (PDA), and Pairwise Distance Test (PDT). Further, the contact map is computed based on CASP criteria by converting the predicted real-valued distance, and it is evaluated using the precision metric. It is observed that precision of long-range top L/5 contact prediction on the CASP13 dataset by the proposed method, RaptorX, Zhang, trRosetta, JinboXu & JinLu, and Deepdist are 0.834, 0.657, 0.70, 0.785, 0.786, and 0.812, respectively. Also, Top-L/5 contact prediction on the CASP14 dataset evaluated using average precision resulted in 0.847, 0.707, 0.752, 0.783, 0.792, 0.817, and 0.825 respectively, corresponding to the proposed method, Zhang, RaptorX, trRosetta, Deepdist, JinboXu & JinLu, and Alphafold2.

Protein secondary structure prediction is essential for understanding protein function and characteristics and can also facilitate drug discovery. Traditional methods for experimentally determining protein structures are both time-consuming and costly. Computational biology offers a viable alternative by predicting protein structures from their sequences. Protein secondary structure is defined by the local spatial arrangement of the protein backbone, resulting from hydrogen bonds between amino acids. In this study, we introduce TransConv, a model that combines transformer models with convolutional blocks to predict protein secondary structures from amino acid sequences. Transformer models are effective at capturing long-range dependencies through self-attention mechanisms. We integrate convolutional blocks into the transformer architecture to improve the detection of important local features. This hybrid model captures both long-range interactions and local features, leading to more accurate predictions of protein secondary structures, thus offering an efficient solution for this critical task. The experimental outcomes on the benchmark datasets depict the superiority of the proposed approach over the state-of-the-art (SOTA) models in the literature.

Accurate prediction of protein secondary structure is essential for accurate sequence alignment, three-dimensional structure modeling, and function prediction. The accuracy of ab initio secondary structure prediction from sequence, however, has only increased from around 77 to 80% over the past decade. Here, we developed a multistep neural-network algorithm by coupling secondary structure prediction with prediction of solvent accessibility and backbone torsion angles in an iterative manner. Our method called SPINE X was applied to a dataset of 2640 proteins (25% sequence identity cutoff) previously built for the first version of SPINE and achieved a 82.0% accuracy based on 10-fold cross validation (Q(3)). Surpassing 81% accuracy by SPINE X is further confirmed by employing an independently built test dataset of 1833 protein chains, a recently built dataset of 1975 proteins and 117 CASP 9 targets (critical assessment of structure prediction techniques) with an accuracy of 81.3%, 82.3% and 81.8%, respectively. The prediction accuracy is further improved to 83.8% for the dataset of 2640 proteins if the DSSP assignment used above is replaced by a more consistent consensus secondary structure assignment method. Comparison to the popular PSIPRED and CASP-winning structure-prediction techniques is made. SPINE X predicts number of helices and sheets correctly for 21.0% of 1833 proteins, compared to 17.6% by PSIPRED. It further shows that SPINE X consistently makes more accurate prediction in helical residues (6%) without over prediction while PSIPRED makes more accurate prediction in coil residues (3-5%) and over predicts them by 7%. SPINE X Server and its training/test datasets are available at http://sparks.informatics.iupui.edu/

Most of the protein structure prediction methods use a multi-step process, which often includes secondary structure prediction, contact prediction, fragment generation, clustering, etc. For many years, secondary structure prediction has been the workhorse for numerous methods aimed at predicting protein structure and function. This paper presents a new mixed integer linear optimization (MILP)-based consensus method: a Consensus scheme based On a mixed integer liNear optimization method for seCOndary stRucture preDiction (CONCORD). Based on seven secondary structure prediction methods, SSpro, DSC, PROF, PROFphd, PSIPRED, Predator and GorIV, the MILP-based consensus method combines the strengths of different methods, maximizes the number of correctly predicted amino acids and achieves a better prediction accuracy. The method is shown to perform well compared with the seven individual methods when tested on the PDBselect25 training protein set using sixfold cross validation. It also performs well compared with another set of 10 online secondary structure prediction servers (including several recent ones) when tested on the CASP9 targets ( http://predictioncenter.org/casp9/ ). The average Q3 prediction accuracy is 83.04 per cent for the sixfold cross validation of the PDBselect25 set and 82.3 per cent for the CASP9 targets. We have developed a MILP-based consensus method for protein secondary structure prediction. A web server, CONCORD, is available to the scientific community at http://helios.princeton.edu/CONCORD .

The accuracy of predicting protein local and global structural properties such as secondary structure and solvent accessible surface area has been stagnant for many years because of the challenge of accounting for non-local interactions between amino acid residues that are close in three-dimensional structural space but far from each other in their sequence positions. All existing machine-learning techniques relied on a sliding window of 10-20 amino acid residues to capture some 'short to intermediate' non-local interactions. Here, we employed Long Short-Term Memory (LSTM) Bidirectional Recurrent Neural Networks (BRNNs) which are capable of capturing long range interactions without using a window. We showed that the application of LSTM-BRNN to the prediction of protein structural properties makes the most significant improvement for residues with the most long-range contacts (|i-j| >19) over a previous window-based, deep-learning method SPIDER2. Capturing long-range interactions allows the accuracy of three-state secondary structure prediction to reach 84% and the correlation coefficient between predicted and actual solvent accessible surface areas to reach 0.80, plus a reduction of 5%, 10%, 5% and 10% in the mean absolute error for backbone ϕ , ψ , θ and τ angles, respectively, from SPIDER2. More significantly, 27% of 182724 40-residue models directly constructed from predicted C α atom-based θ and τ have similar structures to their corresponding native structures (6Å RMSD or less), which is 3% better than models built by ϕ and ψ angles. We expect the method to be useful for assisting protein structure and function prediction. The method is available as a SPIDER3 server and standalone package at http://sparks-lab.org . yaoqi.zhou@griffith.edu.au or yuedong.yang@griffith.edu.au. Supplementary data are available at Bioinformatics online.

The accurate prediction of secondary structures of proteins (SSPs) is a critical challenge in molecular biology and structural bioinformatics. Despite recent advancements, this task remains complex and demands further exploration. This study presents a novel approach to SSP prediction using atom-centric substructural multilevel neighborhoods of atoms (MNA) descriptors for protein molecular fragments. A dataset comprising over 335,000 SSPs, annotated by the Dictionary of Secondary Structure in Proteins (DSSP) software from 37,000 proteins, was constructed from Protein Data Bank (PDB) records with a resolution of 2 Å or better. Protein fragments were converted into structural formulae using the RDKit Python package and stored in SD files using the MOL V3000 format. Classification sequence–structure–property relationships (SSPR) models were developed with varying levels of MNA descriptors and a Bayesian algorithm implemented in MultiPASS software. The average prediction accuracy (AUC) for eight SSP types, calculated via leave-one-out cross-validation, was 0.902. For independent test sets (ASTRAL and CB513 datasets), the best SSPR models achieved AUC, Q3, and Q8 values of 0.860, 77.32%, 70.92% and 0.889, 78.78%, 74.74%, respectively. Based on the created models, a freely available web application MNA-PSS-Pred was developed.

The secondary structure prediction of proteins is a classic topic of computational structural biology with a variety of applications. During the past decade, the accuracy of prediction achieved by state-of-the-art algorithms has been >80%; meanwhile, the time cost of prediction increased rapidly because of the exponential growth of fundamental protein sequence data. Based on literature studies and preliminary observations on the relationships between the size/homology of the fundamental protein dataset and the speed/accuracy of predictions, we raised two hypotheses that might be helpful to determine the main influence factors of the efficiency of secondary structure prediction. Experimental results of size and homology reductions of the fundamental protein dataset supported those hypotheses. They revealed that shrinking the size of the dataset could substantially cut down the time cost of prediction with a slight decrease of accuracy, which could be increased on the contrary by homology reduction of the dataset. Moreover, the Shannon information entropy could be applied to explain how accuracy was influenced by the size and homology of the dataset. Based on these findings, we proposed that a proper combination of size and homology reductions of the protein dataset could speed up the secondary structure prediction while preserving the high accuracy of state-of-the-art algorithms. Testing the proposed strategy with the fundamental protein dataset of the year 2018 provided by the Universal Protein Resource, the speed of prediction was enhanced over 20 folds while all accuracy measures remained equivalently high. These findings are supposed helpful for improving the efficiency of researches and applications depending on the secondary structure prediction of proteins. To make future implementations of the proposed strategy easy, we have established a database of size and homology reduced protein datasets at http://10.life.nctu.edu.tw/UniRefNR.

The secondary structure of a protein is critical for establishing a link between the protein primary and tertiary structures. For this reason, it is important to design methods for accurate protein secondary structure prediction. Most of the existing computational techniques for protein structural and functional prediction are based on machine learning with shallow frameworks. Different deep learning architectures have already been applied to tackle protein secondary structure prediction problem. In this study, deep learning based models, i.e., convolutional neural network and long short-term memory for protein secondary structure prediction were proposed. The input to proposed models is amino acid sequences which were derived from CulledPDB dataset. Hyperparameter tuning with cross validation was employed to attain best parameters for the proposed models. The proposed models enables effective processing of amino acids and attain approximately 87.05% and 87.47% Q3 accuracy of protein secondary structure prediction for convolutional neural network and long short-term memory models, respectively.