An Analysis of Reentrant Loops

BackgroundIntrinsically Disordered Proteins (IDPs) lack an ordered three-dimensional structure and are enriched in various biological processes. The Molecular Recognition Features (MoRFs) are functional regions within IDPs that undergo a disorder-to-order transition on binding to a partner protein. Identifying MoRFs in IDPs using computational methods is a challenging task.MethodsIn this study, we introduce hidden Markov model (HMM) profiles to accurately identify the location of MoRFs in disordered protein sequences. Using windowing technique, HMM profiles are utilised to extract features from protein sequences and support vector machines (SVM) are used to calculate a propensity score for each residue. Two different SVM kernels with high noise tolerance are evaluated with a varying window size and the scores of the SVM models are combined to generate the final propensity score to predict MoRF residues. The SVM models are designed to extract maximal information between MoRF residues, its neighboring regions (Flanks) and the remainder of the sequence (Others).ResultsTo evaluate the proposed method, its performance was compared to that of other MoRF predictors; MoRFpred and ANCHOR. The results show that the proposed method outperforms these two predictors.ConclusionsUsing HMM profile as a source of feature extraction, the proposed method indicates improvement in predicting MoRFs in disordered protein sequences.

BackgroundProfile Hidden Markov Model (HMM) is a powerful statistical model to represent a family of DNA, RNA, and protein sequences. Profile HMM has been widely used in bioinformatics research such as sequence alignment, gene structure prediction, motif identification, protein structure prediction, and biological database search. However, few comprehensive, visual editing tools for profile HMM are publicly available.ResultsWe develop a visual editor for profile Hidden Markov Models (HMMEditor). HMMEditor can visualize the profile HMM architecture, transition probabilities, and emission probabilities. Moreover, it provides functions to edit and save HMM and parameters. Furthermore, HMMEditor allows users to align a sequence against the profile HMM and to visualize the corresponding Viterbi path.ConclusionHMMEditor provides a set of unique functions to visualize and edit a profile HMM. It is a useful tool for biological sequence analysis and modeling. Both HMMEditor software and web service are freely available.

A specific treatment of recurrent structural motifs that represent the local bias information has been proven to be an important ingredient in de novo protein structure predication. Significant majority of methods for local structure are based on building blocks, which still suffer from its inherent discrete nature. Instead of using building blocks, this work presents a new protocol framework for local structural motifs prediction based on the direct locating along protein sequence and probabilistic sampling in a continuous (φ, ψ) space. The protein sequence was first scanned by an algorithm of sliding window with variable length of 7 to 19 residues, to match local segments to one of 82 motifs patterns in the fragment library. Identified segments were then labeled and modeled as the correlations of backbone torsion angles with mixture of bivariate cosine distributions in continuous (φ, ψ) space. 3D conformations of corresponding segments were finally sampled by using a backtrack algorithm to the hidden Markov model with single output of (φ, ψ). For local motifs in 50 proteins of testing set, about 62% of eight-residue segments located with high confidence value were predicted within 1.5 Å of their native structures by the method. Majority of local structural motifs were identified and sampled, which indicates the proposed protocol may at least serve as the foundation to obtain better protein tertiary structure prediction.

The profile hidden Markov model (PHMM) is widely used to assign the protein sequences to their respective families. A major limitation of a PHMM is the assumption that given states the observations (amino acids) are independent. To overcome this limitation, the dependency between amino acids in a multiple sequence alignment (MSA) which is the representative of a PHMM can be appended to the PHMM. Due to the fact that with a MSA, the sequences of amino acids are biologically related, the one-by-one dependency between two amino acids can be considered. In other words, based on the MSA, the dependency between an amino acid and its corresponding amino acid located above can be combined with the PHMM. For this purpose, the new emission probability matrix which considers the one-by-one dependencies between amino acids is constructed. The parameters of a PHMM are of two types; transition and emission probabilities which are usually estimated using an EM algorithm called the Baum-Welch algorithm. We have generalized the Baum-Welch algorithm using similarity emission matrix constructed by integrating the new emission probability matrix with the common emission probability matrix. Then, the performance of similarity emission is discussed by applying it to the top twenty protein families in the Pfam database. We show that using the similarity emission in the Baum-Welch algorithm significantly outperforms the common Baum-Welch algorithm in the task of assigning protein sequences to protein families.

Functional biological sequences, which typically come in families, have retained some level of similarity and function during evolution. Finding consensus regions, alignment of sequences, and identifying the relationship between a sequence and a family allow inferences about the function of the sequences. Profile hidden Markov models (HMMs) are generally used to identify those relationships. A profile HMM can be trained on unaligned members of the family using conventional algorithms such as Baum-Welch, Viterbi, and their modifications. The overall quality of the alignment depends on the quality of the trained model. Unfortunately, the conventional training algorithms converge to suboptimal models most of the time. This work proposes a training algorithm that early identifies many imperfect models. The method is based on the Simulated Annealing approach widely used in discrete optimization problems. The training algorithm is implemented as a component in HMMER. The performance of the algorithm is discussed on protein sequence data.KeywordsSimulated AnnealingHide Markov ModelMultiple AlignmentTraining AlgorithmSimulated Annealing AlgorithmThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Regulation of gene expression influences almost all biological processes in an organism; sequence-specific DNA-binding transcription factors are critical to this control. For most genomes, the repertoire of transcription factors is only partially known. Hitherto transcription factor identification has been largely based on genome annotation pipelines that use pairwise sequence comparisons, which detect only those factors similar to known genes, or on functional classification schemes that amalgamate many types of proteins into the category of ‘transcription factor’. Using a novel transcription factor identification method, the DBD transcription factor database fills this void, providing genome-wide transcription factor predictions for organisms from across the tree of life. The prediction method behind DBD identifies sequence-specific DNA-binding transcription factors through homology using profile hidden Markov models (HMMs) of domains. Thus, it is limited to factors that are homologus to those HMMs. The collection of HMMs is taken from two existing databases (Pfam and SUPERFAMILY), and is limited to models that exclusively detect transcription factors that specifically recognize DNA sequences. It does not include basal transcription factors or chromatin-associated proteins, for instance. Based on comparison with experimentally verified annotation, the prediction procedure is between 95% and 99% accurate. Between one quarter and one-half of our genome-wide predicted transcription factors represent previously uncharacterized proteins. The DBD () consists of predicted transcription factor repertoires for 150 completely sequenced genomes, their domain assignments and the hand curated list of DNA-binding domain HMMs. Users can browse, search or download the predictions by genome, domain family or sequence identifier, view families of transcription factors based on domain architecture and receive predictions for a protein sequence.

InterPro (http://www.ebi.ac.uk/interpro/) is a freely available database used to classify protein sequences into families and to predict the presence of important domains and sites. The resource is based around diagnostic models (profile hidden Markov models, profiles, position-specific scoring matrices and regular expressions) provided by 14 different member databases, against which protein sequences are searched to determine their potential functions. Two recently added member databases, CDD and SLFD, also provide specific residue-level annotation. Their addition has enabled identification of important amino acids, such as those responsible for ligand-binding, protein-protein interactions, or comprising active sites, providing an additional tier to the annotations already provided by InterPro. In a further expansion, InterPro has also added prediction of intrinsically disordered regions (IDRs) – polypeptide segments that have little or no three-dimensional structure. IDRs have a wide range of potential functions, from acting as flexible linkers between domains, to interacting with other proteins and modifying their activity. Due to their bias composition and differing pattern of amino acid conservation, IDRs are hard to model using profile approaches, hence annotation of these regions has been limited to date. To address this, InterPro has integrated the MobiDB Lite tool, which combines eight different prediction methods to generate consensus IDR annotations, focusing on long disordered regions (>20 amino acids). This approach has yielded IDR annotations for ~ 24% of sequences in UniProtKB, covering ~ 5.5% of amino acid residues. Here we describe how the new per-residue and IDR developments in InterPro enable more richly-detailed and informative annotation of protein sequences, and how they can be used to support more specific functional inferences.

In this work we created a sequence model that goes beyond simple linear patterns to model a specific type of higher-order relationship possible in biological sequences. Particularly, we seek models that can account for partially overlaid and interleaved patterns in biological sequences. Our proposed context-switching model (cswHMM) is designed as a variable-order hidden Markov model (HMM) with a specific structure that allows switching control between two or more sub-models.Tests of this approach suggest that a combination of HMMs for protein sequence analysis, such as pattern mining based HMMs or profile HMMs, with the context-switching approach can improve the descriptive ability and performance of the models.

Motivation: One of the most successful methods to date for recognizing protein sequences that are evolutionarily related has been profile hidden Markov models (HMMs). However, these models do not capture pairwise statistical preferences of residues that are hydrogen bonded in beta sheets. These dependencies have been partially captured in the HMM setting by simulated evolution in the training phase and can be fully captured by Markov random fields (MRFs). However, the MRFs can be computationally prohibitive when beta strands are interleaved in complex topologies. We introduce SMURFLite, a method that combines both simplified MRFs and simulated evolution to substantially improve remote homology detection for beta structures. Unlike previous MRF-based methods, SMURFLite is computationally feasible on any beta-structural motif.Results: We test SMURFLite on all propeller and barrel folds in the mainly-beta class of the SCOP hierarchy in stringent cross-validation experiments. We show a mean 26% (median 16%) improvement in area under curve (AUC) for beta-structural motif recognition as compared with HMMER (a well-known HMM method) and a mean 33% (median 19%) improvement as compared with RAPTOR (a well-known threading method) and even a mean 18% (median 10%) improvement in AUC over HHPred (a profile–profile HMM method), despite HHpred's use of extensive additional training data. We demonstrate SMURFLite's ability to scale to whole genomes by running a SMURFLite library of 207 beta-structural SCOP superfamilies against the entire genome of Thermotoga maritima, and make over a 100 new fold predictions.Availability and implementaion: A webserver that runs SMURFLite is available at: http://smurf.cs.tufts.edu/smurflite/Contact: lenore.cowen@tufts.edu; bab@mit.edu

In this paper we propose a new framework for modeling 2D shapes. A shape is first described by a sequence of local features (e.g., curvature) of the shape boundary. The resulting description is then used to build a profile hidden Markov model (PHMM) representation of the shape. PHMMs are a particular type of hidden Markov models (HMMs) with special states and architecture that can tolerate considerable shape contour perturbations, including rigid and non-rigid deformations, occlusions and missing contour parts. Different from traditional HMM-based shape models, the sparseness of the PHMM structure allows efficient inference and learning algorithms for shape modeling and analysis. The new framework can be applied to a wide range of problems, from shape matching and classification to shape segmentation. Our experimental results show the effectiveness and robustness of this new approach in the three application domains.

In protein structure prediction problem, DNA-binding protein identification plays a significant role in various processes like transcription, DNA replication, DNA recombination, repair and modification. It has been a very active area of research to find an effective way to solve DNA-binding protein problem. The experimental methods that are employed for protein structure prediction are quite expensive and time consuming. Most of the methods have yielded better results in extracting evolutionary features. Recently, hidden Markov model (HMM) has been employed to extract features with remarkable increase in the efficiency for identification of DNA-binding proteins. In this study, a novel system based on HMM profile has been proposed to capture distant homology and evolutionary information. The experiments using the HMM profile model have been carried out on independent dataset with prediction accuracy 72% prediction accuracy, which is 3% better compared to the previous attempts. In this study, a comprehensive analysis of HMM profile model is conducted and the results are compared with other traditional models based on performances indices.KeywordsHidden Markov modelDNA-binding proteinProfile HMM

We present RVDB-prot, a database corresponding to the protein equivalent of the nucleic acid reference virus database RVDB. Protein databases can be helpful to perform more sensitive protein sequence comparisons. Similarly to its homologous public repository, RVDB-prot aims to provide reliable and accurately annotated unique entries, while including also an Hidden Markov Model (HMM) protein profiles database for distant protein searching.

We present RVDB-prot, a database corresponding to the protein equivalent of the nucleic acid reference virus database RVDB. Protein databases can be helpful to perform more sensitive protein sequence comparisons. Similarly to its homologous public repository, RVDB-prot aims to provide reliable and accurately annotated unique entries, while including also an Hidden Markov Model (HMM) protein profiles database for distant protein searching.

In this work, we propose a machine learning method to identify protein-protein interacting partners based on domain level knowledge that can take into account information about the interaction sites. The general approach is to use the profile hidden Markov models of protein domains and the known interactions between domains to train a support vector machine. Proteins are characterized by the vectors of fisher scores that are obtained from comparing the protein sequences to the hidden Markov model for a given domain. Protein pairs, represented by concatenation of their respective fisher score vectors, are classified as interacting partners and non interacting partners by a trained SVM. By selecting the fisher scores based on a profile hidden Markov model that differentiates the interaction sites from other residues within the domain, we demonstrated that the prediction accuracy was significantly improved, as measured in a series of cross validation experiments.

This paper shows how the newly developed paradigm of General Fuzzy Automata (GFA) can be used as a biological sequence predictor. We consider the positional correlations of amino acids in a protein family as the basic criteria for prediction and classification of unknown sequences. It will be shown how the GFA formalism can be used as an efficient tool for classification of protein sequences. The results show that this approach predicts the membership of an unknown sequence in a protein family better than profile Hidden Markov Models (HMMs) which are now a popular and putative approach in biological sequence analysis.