Search

In recent years, protein structure problems have become a hotspot for understanding protein folding and function mechanisms. It has been observed that most of the protein structure works rely on and benefit from co-evolutionary information obtained by multiple sequence alignment (MSA). As an example, AlphaFold2 (AF2) is a typical MSA-based protein structure tool which is famous for its high accuracy. As a consequence, these MSA-based methods are limited by the quality of the MSAs. Especially for orphan proteins that have no homologous sequence, AlphaFold2 performs unsatisfactorily as MSA depth decreases, which may pose a barrier to its widespread application in protein mutation and design problems in which there are no rich homologous sequences and rapid prediction is needed. In this paper, we constructed two standard datasets for orphan and de novo proteins which have insufficient/none homology information, called Orphan62 and Design204, respectively, to fairly evaluate the performance of the various methods in this case. Then, depending on whether or not utilizing scarce MSA information, we summarized two approaches, MSA-enhanced and MSA-free methods, to effectively solve the issue without sufficient MSAs. MSA-enhanced model aims to improve poor MSA quality from the data source by knowledge distillation and generation models. MSA-free model directly learns the relationship between residues on enormous protein sequences from pre-trained models, bypassing the step of extracting the residue pair representation from MSA. Next, we evaluated the performance of four MSA-free methods (trRosettaX-Single, TRFold, ESMFold and ProtT5) and MSA-enhanced (Bagging MSA) method compared with a traditional MSA-based method AlphaFold2, in two protein structure-related prediction tasks, respectively. Comparison analyses show that trRosettaX-Single and ESMFold which belong to MSA-free method can achieve fast prediction (⁠|$\sim\! 40$| s) and comparable performance compared with AF2 in tertiary structure prediction, especially for short peptides, |$\alpha $| -helical segments and targets with few homologous sequences. Bagging MSA utilizing MSA enhancement improves the accuracy of our trained base model which is an MSA-based method when poor homology information exists in secondary structure prediction. Our study provides biologists an insight of how to select rapid and appropriate prediction tools for enzyme engineering and peptide drug development. Contact guofei@csu.edu.cn , jj.tang@siat.ac.cn [ABSTRACT FROM AUTHOR]

Simple Summary: Major histocompatibility complex molecules are of significant biological and clinical importance due to their utility in immunotherapy. The prediction of potential MHC binding peptides can estimate a T-cell immune response. The variable length of existing MHC binding peptides creates difficulty for MHC binding prediction algorithms. Thus, we utilized a bilateral and variable long-short term memory neural network to address this specific problem and developed a novel MHC binding prediction tool. As an important part of immune surveillance, major histocompatibility complex (MHC) is a set of proteins that recognize foreign molecules. Computational prediction methods for MHC binding peptides have been developed. However, existing methods share the limitation of fixed peptide sequence length, which necessitates the training of models by peptide length or prediction with a length reduction technique. Using a bidirectional long short-term memory neural network, we constructed BVMHC, an MHC class I and II binding prediction tool that is independent of peptide length. The performance of BVMHC was compared to seven MHC class I prediction tools and three MHC class II prediction tools using eight performance criteria independently. BVMHC attained the best performance in three of the eight criteria for MHC class I, and the best performance in four of the eight criteria for MHC class II, including accuracy and AUC. Furthermore, models for non-human species were also trained using the same strategy and made available for applications in mice, chimpanzees, macaques, and rats. BVMHC is composed of a series of peptide length independent MHC class I and II binding predictors. Models from this study have been implemented in an online web portal for easy access and use. [ABSTRACT FROM AUTHOR]

Major histocompatibility complex (MHC) possesses important research value in the treatment of complex human diseases. A plethora of computational tools has been developed to predict MHC class I binders. Here, we comprehensively reviewed 27 up-to-date MHC I binding prediction tools developed over the last decade, thoroughly evaluating feature representation methods, prediction algorithms and model training strategies on a benchmark dataset from Immune Epitope Database. A common limitation was identified during the review that all existing tools can only handle a fixed peptide sequence length. To overcome this limitation, we developed a bilateral and variable long short-term memory (BVLSTM)-based approach, named BVLSTM-MHC. It is the first variable-length MHC class I binding predictor. In comparison to the 10 mainstream prediction tools on an independent validation dataset, BVLSTM-MHC achieved the best performance in six out of eight evaluated metrics. A web server based on the BVLSTM-MHC model was developed to enable accurate and efficient MHC class I binder prediction in human, mouse, macaque and chimpanzee. [ABSTRACT FROM AUTHOR]

Background: Protein subcellular localization prediction plays an important role in biology research. Since traditional methods are laborious and time-consuming, many machine learning-based prediction methods have been proposed. However, most of the proposed methods ignore the evolution information of proteins. In order to improve the prediction accuracy, we present a deep learning-based method to predict protein subcellular locations. Results: Our method utilizes not only amino acid compositions sequence but also evolution matrices of proteins. Our method uses a bidirectional long short-term memory network that processes the entire protein sequence and a convolutional neural network that extracts features from protein sequences. The position specific scoring matrix is used as a supplement to protein sequences. Our method was trained and tested on two benchmark datasets. The experiment results show that our method yields accurate results on the two datasets with an average precision of 0.7901, ranking loss of 0.0758 and coverage of 1.2848. Conclusion: The experiment results show that our method outperforms five methods currently available. According to those experiments, we can see that our method is an acceptable alternative to predict protein subcellular location. [ABSTRACT FROM AUTHOR]

RNA-binding proteins play an important role in the biological process. However, the traditional experiment technology to predict RNA-binding residues is time-consuming and expensive, so the development of an effective computational approach can provide a strategy to solve this issue. In recent years, most of the computational approaches are constructed on protein sequence information, but the protein structure has not been considered. In this paper, we use a novel computational model of RNA-binding residues prediction, using protein sequence and structure information. Our hybrid features are encoded by local sequence and structure feature extraction models. Our predictor is built by employing the Granular Multiple Kernel Support Vector Machine with Repetitive Under-sampling (GMKSVM-RU). In order to evaluate our method, we use fivefold cross-validation on the RBP129, our method achieves better experimental performance with MCC of 0.3367 and accuracy of 88.84%. In order to further evaluate our model, an independent data set (RBP60) is employed, and our method achieves MCC of 0.3921 and accuracy of 87.52%. Above results demonstrate that integrating sequence and structure information is beneficial to improve the prediction ability of RNA-binding residues. [ABSTRACT FROM AUTHOR]

Background: DNA-Binding Proteins (DBP) plays a pivotal role in biological system. A mounting number of researchers are studying the mechanism and detection methods. To detect DBP, the tradition experimental method is time-consuming and resource-consuming. In recent years, Machine Learning methods have been used to detect DBP. However, it is difficult to adequately describe the information of proteins in predicting DNA-binding proteins. In this study, we extract six features from protein sequence and use Multiple Kernel Learning-based on Centered Kernel Alignment to integrate these features. The integrated feature is fed into Support Vector Machine to build predictive model and detect new DBP. Results: In our work, date sets of PDB1075 and PDB186 are employed to test our method. From the results, our model obtains better results (accuracy) than other existing methods on PDB1075 ( 84.19 % ) and PDB186 ( 83.7 % ), respectively. Conclusion: Multiple kernel learning could fuse the complementary information between different features. Compared with existing methods, our method achieves comparable and best results on benchmark data sets. [ABSTRACT FROM AUTHOR]

Since the importance of DNA-binding proteins in multiple biomolecular functions has been recognized, an increasing number of researchers are attempting to identify DNA-binding proteins. In recent years, the machine learning methods have become more and more compelling in the case of protein sequence data soaring, because of their favorable speed and accuracy. In this paper, we extract three features from the protein sequence, namely NMBAC (Normalized Moreau-Broto Autocorrelation), PSSM-DWT (Position-specific scoring matrix—Discrete Wavelet Transform), and PSSM-DCT (Position-specific scoring matrix—Discrete Cosine Transform). We also employ feature selection algorithm on these feature vectors. Then, these features are fed into the training SVM (support vector machine) model as classifier to predict DNA-binding proteins. Our method applys three datasets, namely PDB1075, PDB594 and PDB186, to evaluate the performance of our approach. The PDB1075 and PDB594 datasets are employed for Jackknife test and the PDB186 dataset is used for the independent test. Our method achieves the best accuracy in the Jacknife test, from 79.20% to 86.23% and 80.5% to 86.20% on PDB1075 and PDB594 datasets, respectively. In the independent test, the accuracy of our method comes to 76.3%. The performance of independent test also shows that our method has a certain ability to be effectively used for DNA-binding protein prediction. The data and source code are at . [ABSTRACT FROM AUTHOR]

Abstract: Bacterial intergenic spacers are non-coding genomic regions enriched with cis-regulatory elements for gene expression. A population genetics approach was used to investigate the evolutionary force shaping the genetic diversity of intergenic spacers among 13 genomes of group A streptococcus (GAS). Analysis of 590 genes and their linked 5′ intergenic spacers showed reduced nucleotide diversity in spacers compared to synonymous nucleotide diversity in protein-coding regions, suggestive of past purifying selection on spacers. Certain spacers showed elevated nucleotide diversity indicative of past homologous recombination with divergent genotypes. In addition, analysis of the difference between mean nucleotide difference and number of segregating sites showed evidence of an excess of rare variants both at nonsynonymous sites in genes and at sites in spacers, which is evidence that there are numerous slightly deleterious variants in GAS populations with potential effects on both protein sequences and gene expression. [Copyright &y& Elsevier]