Protein Remote Homology Detection Research Articles

PreHom-PCLM: protein remote homology detection by combing motifs and protein cubic language model.

Protein remote homology detection is essential for structure prediction, function prediction, disease mechanism understanding, etc. The remote homology relationship depends on multiple protein properties, such as structural information and local sequence patterns. Previous studies have shown the challenges for predicting remote homology relationship by protein features at sequence level (e.g. position-specific score matrix). Protein motifs have been used in structure and function analysis due to their unique sequence patterns and implied structural information. Therefore, designing a usable architecture to fuse multiple protein properties based on motifs is urgently needed to improve protein remote homology detection performance. To make full use of the characteristics of motifs, we employed the language model called the protein cubic language model (PCLM). It combines multiple properties by constructing a motif-based neural network. Based on the PCLM, we proposed a predictor called PreHom-PCLM by extracting and fusing multiple motif features for protein remote homology detection. PreHom-PCLM outperforms the other state-of-the-art methods on the test set and independent test set. Experimental results further prove the effectiveness of multiple features fused by PreHom-PCLM for remote homology detection. Furthermore, the protein features derived from the PreHom-PCLM show strong discriminative power for proteins from different structural classes in the high-dimensional space. Availability and Implementation: http://bliulab.net/PreHom-PCLM.

Protein remote homology detection and structural alignment using deep learning.

Exploiting sequence-structure-function relationships in biotechnology requires improved methods for aligning proteins that have low sequence similarity to previously annotated proteins. We develop two deep learning methods to address this gap, TM-Vec and DeepBLAST. TM-Vec allows searching for structure-structure similarities in large sequence databases. It is trained to accurately predict TM-scores as a metric of structural similarity directly from sequence pairs without the need for intermediate computation or solution of structures. Once structurally similar proteins have been identified, DeepBLAST can structurally align proteins using only sequence information by identifying structurally homologous regions between proteins. It outperforms traditional sequence alignment methods and performs similarly to structure-based alignment methods. We show the merits of TM-Vec and DeepBLAST on a variety of datasets, including better identification of remotely homologous proteins compared with state-of-the-art sequence alignment and structure prediction methods.

BioSeq-Diabolo: Biological sequence similarity analysis using Diabolo.

As the key for biological sequence structure and function prediction, disease diagnosis and treatment, biological sequence similarity analysis has attracted more and more attentions. However, the exiting computational methods failed to accurately analyse the biological sequence similarities because of the various data types (DNA, RNA, protein, disease, etc) and their low sequence similarities (remote homology). Therefore, new concepts and techniques are desired to solve this challenging problem. Biological sequences (DNA, RNA and protein sequences) can be considered as the sentences of "the book of life", and their similarities can be considered as the biological language semantics (BLS). In this study, we are seeking the semantics analysis techniques derived from the natural language processing (NLP) to comprehensively and accurately analyse the biological sequence similarities. 27 semantics analysis methods derived from NLP were introduced to analyse biological sequence similarities, bringing new concepts and techniques to biological sequence similarity analysis. Experimental results show that these semantics analysis methods are able to facilitate the development of protein remote homology detection, circRNA-disease associations identification and protein function annotation, achieving better performance than the other state-of-the-art predictors in the related fields. Based on these semantics analysis methods, a platform called BioSeq-Diabolo has been constructed, which is named after a popular traditional sport in China. The users only need to input the embeddings of the biological sequence data. BioSeq-Diabolo will intelligently identify the task, and then accurately analyse the biological sequence similarities based on biological language semantics. BioSeq-Diabolo will integrate different biological sequence similarities in a supervised manner by using Learning to Rank (LTR), and the performance of the constructed methods will be evaluated and analysed so as to recommend the best methods for the users. The web server and stand-alone package of BioSeq-Diabolo can be accessed at http://bliulab.net/BioSeq-Diabolo/server/.

DeepRHD: An efficient hybrid feature extraction technique for protein remote homology detection using deep learning strategies

In computational biology, the Protein Remote homology Detection technique (PRHD) has got undeniable significance. It is mostly important for structure and function identification of a protein sequence. The previous years have seen a challenge that lacks postulating a correlation among the sequences. However, the sequences are of variable length. Thereby, it inhibits the proper derivation of evolutionary information among the sequences. The challenges are the usage of physico-chemical properties as a source to get the evolutionary information and the number of sequences generated every day. This however facilitates a new technique to integrate huge amount of data with a massive feature set. In this article, a new and efficient technique is proposed to predict homology for distantly located sequences of proteins. Deep neural network(CNN-GRU model) is used for the classification of the protein sequences. This is based on different protein families and methods of feature extraction.The efficiency of the proposed model DeepRHD is tested on average 8000 sequences per superfamily taken from SCOP benchmark dataset and the results shows that the proposed model is better than other state of art methods. This model is useful in detecting diseases like sickle cell anemia and influenza and developing a drug thereafter.

PHR-search: a search framework for protein remote homology detection based on the predicted protein hierarchical relationships.

Protein remote homology detection is one of the most fundamental research tool for protein structure and function prediction. Most search methods for protein remote homology detection are evaluated based on the Structural Classification of Proteins-extended (SCOPe) benchmark, but the diverse hierarchical structure relationships between the query protein and candidate proteins are ignored by these methods. In order to further improve the predictive performance for protein remote homology detection, a search framework based on the predicted protein hierarchical relationships (PHR-search) is proposed. In the PHR-search framework, the superfamily level prediction information is obtained by extracting the local and global features of the Hidden Markov Model (HMM) profile through a convolution neural network and it is converted to the fold level and class level prediction information according to the hierarchical relationships of SCOPe. Based on these predicted protein hierarchical relationships, filtering strategy and re-ranking strategy are used to construct the two-level search of PHR-search. Experimental results show that the PHR-search framework achieves the state-of-the-art performance by employing five basic search methods, including HHblits, JackHMMER, PSI-BLAST, DELTA-BLAST and PSI-BLASTexB. Furthermore, the web server of PHR-search is established, which can be accessed at http://bliulab.net/PHR-search.

Protein remote homology detection combining PCA and multiobjective optimization tools

Protein remote homology detection combining PCA and multiobjective optimization tools

S2L-PSIBLAST: a supervised two-layer search framework based on PSI-BLAST for protein remote homology detection.

Protein remote homology detection is a challenging task for the studies of protein evolutionary relationships. PSI-BLAST is an important and fundamental search method for detecting homology proteins. Although many improved versions of PSI-BLAST have been proposed, their performance is limited by the search processes of PSI-BLAST. For further improving the performance of PSI-BLAST for protein remote homology detection, a supervised two-layer search framework based on PSI-BLAST (S2L-PSIBLAST) is proposed. S2L-PSIBLAST consists of a two-level search: the first-level search provides high-quality search results by using SMI-BLAST framework and double-link strategy to filter the non-homology protein sequences, the second-level search detects more homology proteins by profile-link similarity, and more accurate ranking lists for those detected protein sequences are obtained by learning to rank strategy. Experimental results on the updated version of Structural Classification of Proteins-extended benchmark dataset show that S2L-PSIBLAST not only obviously improves the performance of PSI-BLAST, but also achieves better performance on two improved versions of PSI-BLAST: DELTA-BLAST and PSI-BLASTexB. http://bliulab.net/S2L-PSIBLAST. Supplementary data are available at Bioinformatics online.

ProtRe-CN: Protein Remote Homology Detection by Combining Classification Methods and Network Methods via Learning to Rank.

Protein remote homology detection is one of fundamental research tasks for downstream analysis (i.e., protein structure and function prediction). Many advanced methods are proposed from different views with complementary detection ability, such as the classification method, the network method, and the ranking method. A framework integrating these heterogeneous methods is urgently desired to reduce the false positive rate and predictive bias. We propose a novel ranking method called ProtRe-CN by fusing the classification methods and network methods via Learning to Rank. Experimental results on the benchmark dataset and the independent dataset show that ProtRe-CN outperforms other existing state-of-the-art predictors. ProtRe-CN improves the detective performance via correcting the false positives in the ranking list by combining the heterogeneous methods. The web server of ProtRe-CN can be accessed at http://bliulab.net/ProtRe-CN.

FastSK: fast sequence analysis with gapped string kernels.

Gapped k-mer kernels with support vector machines (gkm-SVMs) have achieved strong predictive performance on regulatory DNA sequences on modestly sized training sets. However, existing gkm-SVM algorithms suffer from slow kernel computation time, as they depend exponentially on the sub-sequence feature length, number of mismatch positions, and the task's alphabet size. In this work, we introduce a fast and scalable algorithm for calculating gapped k-mer string kernels. Our method, named FastSK, uses a simplified kernel formulation that decomposes the kernel calculation into a set of independent counting operations over the possible mismatch positions. This simplified decomposition allows us to devise a fast Monte Carlo approximation that rapidly converges. FastSK can scale to much greater feature lengths, allows us to consider more mismatches, and is performant on a variety of sequence analysis tasks. On multiple DNA transcription factor binding site prediction datasets, FastSK consistently matches or outperforms the state-of-the-art gkmSVM-2.0 algorithms in area under the ROC curve, while achieving average speedups in kernel computation of ∼100× and speedups of ∼800× for large feature lengths. We further show that FastSK outperforms character-level recurrent and convolutional neural networks while achieving low variance. We then extend FastSK to 7 English-language medical named entity recognition datasets and 10 protein remote homology detection datasets. FastSK consistently matches or outperforms these baselines. Our algorithm is available as a Python package and as C++ source code at https://github.com/QData/FastSK. Supplementary data are available at Bioinformatics online.

ReFold-MAP: Protein remote homology detection and fold recognition based on features extracted from profiles

Protein remote homology detection and protein fold recognition are two important tasks in protein structure and function prediction. There are three kinds of methods in this field, including the discriminative methods, the alignment methods, and the ranking methods. In this study, a new discriminative method called ReFold-MAP is proposed. The proposed method extracts comprehensive features based on three profile-based features: Motif-PSSM, ACC-PSSM, and PDT-profile. We call these features as MAP features, which incorporate the structural motif kernel information, the evolutionary information, and the sequence information. The experiments prove that ReFold-MAP outperforms other approaches. Therefore, ReFold-MAP will be a useful tool for protein remote homology detection and fold recognition.

SMI-BLAST: a novel supervised search framework based on PSI-BLAST for protein remote homology detection.

As one of the most important and widely used mainstream iterative search tool for protein sequence search, an accurate Position-Specific Scoring Matrix (PSSM) is the key of PSI-BLAST. However, PSSMs containing non-homologous information obviously reduce the performance of PSI-BLAST for protein remote homology. To further study this problem, we summarize three types of Incorrectly Selected Homology (ISH) errors in PSSMs. A new search tool Supervised-Manner-based Iterative BLAST (SMI-BLAST) is proposed based on PSI-BLAST for solving these errors. SMI-BLAST obviously outperforms PSI-BLAST on the Structural Classification of Proteins-extended (SCOPe) dataset. Compared with PSI-BLAST on the ISH error subsets of SCOPe dataset, SMI-BLAST detects 1.6-2.87 folds more remote homologous sequences, and outperforms PSI-BLAST by 35.66% in terms of ROC1 scores. Furthermore, this framework is applied to JackHMMER, DELTA-BLAST and PSI-BLASTexB, and their performance is further improved. User-friendly webservers for SMI-BLAST, JackHMMER, DELTA-BLAST and PSI-BLASTexB are established at http://bliulab.net/SMI-BLAST/, by which the users can easily get the results without the need to go through the mathematical details. Supplementary data are available at Bioinformatics online.

PL-search: a profile-link-based search method for protein remote homology detection

Protein remote homology detection is a fundamental and important task for protein structure and function analysis. Several search methods have been proposed to improve the detection performance of the remote homologues and the accuracy of ranking lists. The position-specific scoring matrix (PSSM) profile and hidden Markov model (HMM) profile can contribute to improving the performance of the state-of-the-art search methods. In this paper, we improved the profile-link (PL) information for constructing PSSM or HMM profiles, and proposed a PL-based search method (PL-search). In PL-search, more robust PLs are constructed through the double-link and iterative extending strategies, and an accurate similarity score of sequence pairs is calculated from the two-level Jaccard distance for remote homologues. We tested our method on two widely used benchmark datasets. Our results show that whether HHblits, JackHMMER or position-specific iterated-BLAST is used, PL-search obviously improves the search performance in terms of ranking quality as well as the number of detected remote homologues. For ease of use of PL-search, both its stand-alone tool and the web server are constructed, which can be accessed at http://bliulab.net/PL-search/.

A dissimilarity-based multiple instance learning approach for protein remote homology detection

We study the problem of Protein Remote Homology Detection, which assesses the functional similarity of two proteins. We approach this as a problem of binary multiple-instance learning (MIL) that aims to distinguish between homologous and non-homologous proteins. The particular MIL approach employed is based on the dissimilarity representation in which various schemes of combining N-gram representations are considered. This approach allows us to cope with longer N-grams, capturing a richer biological context, and results in versatile framework offering competitive performance compared to state of the art.

ProtDec-LTR3.0: Protein Remote Homology Detection by Incorporating Profile-Based Features Into Learning to Rank

Protein remote homology detection is one of the most challenging problems in the field of protein sequence analysis, which is an important step for both theoretical research (such as the understanding of structures and functions of proteins) and drug design. Previous studies have shown that combining different ranking methods via learning to the rank algorithm is an effective strategy for remote protein homology detection, and the performance can be further improved by the protein similarity networks. In this paper, we improved the ProtDec-LTR1.0 and ProtDec-LTR2.0 predictors by incorporating three profile-based features (Top-1-gram, Top-2-gram, and ACC) into the framework of learning to rank via feature mapping strategies. The predictive performance was further refined by the pagerank (PR) algorithm and hyperlink-induced topic search (HITS) algorithm. Finally, a predictor called ProtDec-LTR3.0 was proposed. Rigorous tests on two widely used benchmark datasets showed that the ProtDec-LTR3.0 predictor outperformed both ProtDec-LTR1.0 and ProtDec-LTR2.0, and other nine existing state-of-the-art predictors, indicating that the ProtDec-LTR3.0 is an efficient method for protein remote homology detection, and will become a useful tool for protein sequence analysis. A user-friendly web server of the ProtDec-LTR3.0 predictor was established for the convenience of users, which can be accessed at http://bliulab.net/ProtDec-LTR3.0/.

HITS-PR-HHblits: protein remote homology detection by combining PageRank and Hyperlink-Induced Topic Search.

As one of the most important fundamental problems in protein sequence analysis, protein remote homology detection is critical for both theoretical research (protein structure and function studies) and real world applications (drug design). Although several computational predictors have been proposed, their detection performance is still limited. In this study, we treat protein remote homology detection as a document retrieval task, where the proteins are considered as documents and its aim is to find the highly related documents with the query documents in a database. A protein similarity network was constructed based on the true labels of proteins in the database, and the query proteins were then connected into the network based on the similarity scores calculated by three ranking methods, including PSI-BLAST, Hmmer and HHblits. The PageRank algorithm and Hyperlink-Induced Topic Search (HITS) algorithm were respectively performed on this network to move the homologous proteins of query proteins to the neighbors of the query proteins in the network. Finally, PageRank and HITS algorithms were combined, and a predictor called HITS-PR-HHblits was proposed to further improve the predictive performance. Tested on the SCOP and SCOPe benchmark datasets, the experimental results showed that the proposed protocols outperformed other state-of-the-art methods. For the convenience of the most experimental scientists, a web server for HITS-PR-HHblits was established at http://bioinformatics.hitsz.edu.cn/HITS-PR-HHblits, by which the users can easily get the results without the need to go through the mathematical details. The HITS-PR-HHblits predictor is a protocol for protein remote homology detection using different sets of programs, which will become a very useful computational tool for proteome analysis.

Using Grey Model to Predict Protein Remote Homologous Family

Protein remote homology detection is the most basic and core problems of protein structure and function research. The purpose of protein remote homology detection to detect the remote evolutionary relationship between proteins by computation methods. At present, there are many methods for remote homology detection of proteins, but some methods are not very effective. In bioinformatics, it is urgent to further improve the performance of protein remote homology detection. In this study, we propose a new model called PHom-GRA to detect protein remote homology, which is the integration of various ranking methods via using grey relational analysis. Our experiment constructs benchmark dataset with lower homology, in which any two proteins have not more than 40% identity or homology. We achieve an ROC1 score of 0.7372 and an ROC50 score of 0.7968 in jack-knife test.

LZW-Kernel: fast kernel utilizing variable length code blocks from LZW compressors for protein sequence classification.

Bioinformatics studies often rely on similarity measures between sequence pairs, which often pose a bottleneck in large-scale sequence analysis. Here, we present a new convolutional kernel function for protein sequences called the Lempel-Ziv-Welch (LZW)-Kernel. It is based on code words identified with the LZW universal text compressor. The LZW-Kernel is an alignment-free method, it is always symmetric, is positive, always provides 1.0 for self-similarity and it can directly be used with Support Vector Machines (SVMs) in classification problems, contrary to normalized compression distance, which often violates the distance metric properties in practice and requires further techniques to be used with SVMs. The LZW-Kernel is a one-pass algorithm, which makes it particularly plausible for big data applications. Our experimental studies on remote protein homology detection and protein classification tasks reveal that the LZW-Kernel closely approaches the performance of the Local Alignment Kernel (LAK) and the SVM-pairwise method combined with Smith-Waterman (SW) scoring at a fraction of the time. Moreover, the LZW-Kernel outperforms the SVM-pairwise method when combined with Basic Local Alignment Search Tool (BLAST) scores, which indicates that the LZW code words might be a better basis for similarity measures than local alignment approximations found with BLAST. In addition, the LZW-Kernel outperforms n-gram based mismatch kernels, hidden Markov model based SAM and Fisher kernel and protein family based PSI-BLAST, among others. Further advantages include the LZW-Kernel's reliance on a simple idea, its ease of implementation, and its high speed, three times faster than BLAST and several magnitudes faster than SW or LAK in our tests. LZW-Kernel is implemented as a standalone C code and is a free open-source program distributed under GPLv3 license and can be downloaded from https://github.com/kfattila/LZW-Kernel. Supplementary data are available at Bioinformatics Online.

ProtDet-CCH: Protein Remote Homology Detection by Combining Long Short-Term Memory and Ranking Methods.

As one of the most challenging tasks in sequence analysis, protein remote homology detection has been extensively studied. Methods based on discriminative models and ranking approaches have achieved the state-of-the-art performance, and these two kinds of methods are complementary. In this study, three LSTM models have been applied to construct the predictors for protein remote homology detection, including ULSTM, BLSTM, and CNN-BLSTM. They are able to automatically extract the local and global sequence order information. Combined with PSSMs, the CNN-BLSTM achieved the best performance among the three LSTM-based models. We named this method as CNN-BLSTM-PSSM. Finally, a new method called ProtDet-CCH was proposed by combining CNN-BLSTM-PSSM and a ranking method HHblits. Tested on a widely used SCOP benchmark dataset, ProtDet-CCH achieved an ROC score of 0.998, and an ROC50 score of 0.982, significantly outperforming other existing state-of-the-art methods. Experimental results on two updated SCOPe independent datasets showed that ProtDet-CCH can achieve stable performance. Furthermore, our method can provide useful insights for studying the features and motifs of protein families and superfamilies. It is anticipated that ProtDet-CCH will become a very useful tool for protein remote homology detection.

Protein Remote Homology Detection and Fold Recognition Based on Sequence-Order Frequency Matrix.

Protein remote homology detection and fold recognition are two critical tasks for the studies of protein structures and functions. Currently, the profile-based methods achieve the state-of-the-art performance in these fields. However, the widely used sequence profiles, like position-specific frequency matrix (PSFM) and position-specific scoring matrix (PSSM), ignore the sequence-order effects along protein sequence. In this study, we have proposed a novel profile, called sequence-order frequency matrix (SOFM), to extract the sequence-order information of neighboring residues from multiple sequence alignment (MSA). Combined with two profile feature extraction approaches, top-n-grams and the Smith-Waterman algorithm, the SOFMs are applied to protein remote homology detection and fold recognition, and two predictors called SOFM-Top and SOFM-SW are proposed. Experimental results show that SOFM contains more information content than other profiles, and these two predictors outperform other state-of-the-art methods. It is anticipated that SOFM will become a very useful profile in the studies of protein structures and functions.

Protein remote homology detection based on bidirectional long short-term memory

BackgroundProtein remote homology detection plays a vital role in studies of protein structures and functions. Almost all of the traditional machine leaning methods require fixed length features to represent the protein sequences. However, it is never an easy task to extract the discriminative features with limited knowledge of proteins. On the other hand, deep learning technique has demonstrated its advantage in automatically learning representations. It is worthwhile to explore the applications of deep learning techniques to the protein remote homology detection.ResultsIn this study, we employ the Bidirectional Long Short-Term Memory (BLSTM) to learn effective features from pseudo proteins, also propose a predictor called ProDec-BLSTM: it includes input layer, bidirectional LSTM, time distributed dense layer and output layer. This neural network can automatically extract the discriminative features by using bidirectional LSTM and the time distributed dense layer.ConclusionExperimental results on a widely-used benchmark dataset show that ProDec-BLSTM outperforms other related methods in terms of both the mean ROC and mean ROC50 scores. This promising result shows that ProDec-BLSTM is a useful tool for protein remote homology detection. Furthermore, the hidden patterns learnt by ProDec-BLSTM can be interpreted and visualized, and therefore, additional useful information can be obtained.