PredictProtein is a meta-service for sequence analysis that has been predicting structural and functional features of proteins since 1992. Queried with a protein sequence it returns: multiple ...sequence alignments, predicted aspects of structure (secondary structure, solvent accessibility, transmembrane helices (TMSEG) and strands, coiled-coil regions, disulfide bonds and disordered regions) and function. The service incorporates analysis methods for the identification of functional regions (ConSurf), homology-based inference of Gene Ontology terms (metastudent), comprehensive subcellular localization prediction (LocTree3), protein-protein binding sites (ISIS2), protein-polynucleotide binding sites (SomeNA) and predictions of the effect of point mutations (non-synonymous SNPs) on protein function (SNAP2). Our goal has always been to develop a system optimized to meet the demands of experimentalists not highly experienced in bioinformatics. To this end, the PredictProtein results are presented as both text and a series of intuitive, interactive and visually appealing figures. The web server and sources are available at http://ppopen.rostlab.org.
This study is motivated by the following three considerations: a) the physico-chemical properties of transmembrane (TM) proteins are distinctly different from those of globular proteins, ...necessitating the development of specialized structure prediction techniques, b) for many structural features no specialized predictors for TM proteins are available at all, and c) deep learning algorithms allow to automate the feature engineering process and thus facilitate the development of multi-target methods for predicting several protein properties at once. We present AllesTM, an integrated tool to predict almost all structural features of transmembrane proteins that can be extracted from atomic coordinate data. It blends several machine learning algorithms: random forests and gradient boosting machines, convolutional neural networks in their original form as well as those enhanced by dilated convolutions and residual connections, and, finally, long short-term memory architectures. AllesTM outperforms other available methods in predicting residue depth in the membrane, flexibility, topology, relative solvent accessibility in its bound state, while in torsion angles, secondary structure and monomer relative solvent accessibility prediction it lags only slightly behind the currently leading technique SPOT-1D. High accuracy on a multitude of prediction targets and easy installation make AllesTM a one-stop shop for many typical problems in the structural bioinformatics of transmembrane proteins. In addition to presenting a highly accurate prediction method and eliminating the need to install and maintain many different software tools, we also provide a comprehensive overview of the impact of different machine learning algorithms and parameter choices on the prediction performance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Any method that de novo predicts protein function should do better than random. More challenging, it also ought to outperform simple homology-based inference.
Here, we describe a few methods that ...predict protein function exclusively through homology. Together, they set the bar or lower limit for future improvements.
During the development of these methods, we faced two surprises. Firstly, our most successful implementation for the baseline ranked very high at CAFA1. In fact, our best combination of homology-based methods fared only slightly worse than the top-of-the-line prediction method from the Jones group. Secondly, although the concept of homology-based inference is simple, this work revealed that the precise details of the implementation are crucial: not only did the methods span from top to bottom performers at CAFA, but also the reasons for these differences were unexpected. In this work, we also propose a new rigorous measure to compare predicted and experimental annotations. It puts more emphasis on the details of protein function than the other measures employed by CAFA and may best reflect the expectations of users. Clearly, the definition of proper goals remains one major objective for CAFA.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Regulated intramembrane proteolysis (RIP) is a critical mechanism for intercellular communication and regulates the function of membrane proteins through sequential proteolysis. RIP typically starts ...with ectodomain shedding of membrane proteins by extracellular membrane-bound proteases followed by intramembrane proteolysis of the resulting membrane-tethered fragment. However, for the majority of RIP proteases the corresponding substrates and thus, their functions, remain unknown. Proteome-wide identification of RIP protease substrates is possible by mass spectrometry-based quantitative comparison of RIP substrates or their cleavage products between different biological states. However, this requires quantification of peptides from only the ectodomain or cytoplasmic domain. Current analysis software does not allow matching peptides to either domain. Here we present the QARIP (Quantitative Analysis of Regulated Intramembrane Proteolysis) web server which matches identified peptides to the protein transmembrane topology. QARIP allows determination of quantitative ratios separately for the topological domains (cytoplasmic, ectodomain) of a given protein and is thus a powerful tool for quality control, improvement of quantitative ratios and identification of novel substrates in proteomic RIP datasets. To our knowledge, the QARIP web server is the first tool directly addressing the phenomenon of RIP. The web server is available at http://webclu.bio.wzw.tum.de/qarip/. This website is free and open to all users and there is no login requirement.
Accurate prediction of intra-molecular interactions from amino acid sequence is an important pre-requisite for obtaining high-quality protein models. Over the recent years, remarkable progress in ...this area has been achieved through the application of novel co-variation algorithms, which eliminate transitive evolutionary connections between residues. In this work we present a new contact prediction method for α-helical transmembrane proteins, MemConP, in which evolutionary couplings are combined with a machine learning approach. MemConP achieves a substantially improved accuracy (precision: 56.0%, recall: 17.5%, MCC: 0.288) compared to the use of either machine learning or co-evolution methods alone. The method also achieves 91.4% precision, 42.1% recall and a MCC of 0.490 in predicting helix–helix interactions based on predicted contacts. The approach was trained and rigorously benchmarked by cross-validation and independent testing on up-to-date non-redundant datasets of 90 and 30 experimental three dimensional structures, respectively. MemConP is a standalone tool that can be downloaded together with the associated training data from http://webclu.bio.wzw.tum.de/MemConP.
Display omitted
•Transmembrane protein interaction sites are best predicted by a specific classifier.•Separate models for predicted and structure determined transmembrane regions improve ...accuracy.•Using co-evolution as a feature compensates for the restricted amino acid composition in transmembrane segments.
Many integral membrane proteins, just like their globular counterparts, form either transient or permanent multi-subunit complexes to fulfill specific cellular roles. Although numerous interactions between these proteins have been experientially determined, the structural coverage of the complexes is very low. Therefore, the computational identification of the amino acid residues involved in the interaction interfaces is a crucial step towards the functional annotation of all membrane proteins.Here, we present MBPred, a sequence-based method for predicting the interface residues in transmembrane proteins. An unique feature of our method is that it contains separate random forest models for two different use cases: (a) when the location of transmembrane regions is precisely known from a crystal structure, and (b) when it is predicted from sequence. In stark contrast to the aqueous-exposed protein segments, we found that the interaction sites located in the membrane are not enriched for evolutionary conservation, most likely due to their restricted amino acid composition or their random distribution among buried and exposed residues. On the other hand, residue co-evolution proved to be a very informative feature which has not so far been used for predicting interaction sites in individual proteins. MBPred reaches AUC, precision and recall values of 0.79/0.73, 0.69/0.51 and 0.55/0.48 on the cross-validation and independent test dataset, respectively, thus outperforming the previously published method of Bordner as well as all methods trained on globular proteins. Moreover, we show that for the majority of complete interface patches, the method captures more than 50% of the involved residues.
Automated annotation of protein function is challenging. As the number of sequenced genomes rapidly grows, the overwhelming majority of protein products can only be annotated computationally. If ...computational predictions are to be relied upon, it is crucial that the accuracy of these methods be high. Here we report the results from the first large-scale community-based critical assessment of protein function annotation (CAFA) experiment. Fifty-four methods representing the state of the art for protein function prediction were evaluated on a target set of 866 proteins from 11 organisms. Two findings stand out: (i) today's best protein function prediction algorithms substantially outperform widely used first-generation methods, with large gains on all types of targets; and (ii) although the top methods perform well enough to guide experiments, there is considerable need for improvement of currently available tools.
Abstract
Motivation
Existing sources of experimental mutation data do not consider the structural environment of amino acid substitutions and distinguish between soluble and membrane proteins. They ...also suffer from a number of further limitations, including data redundancy, lack of disease classification, incompatible information content, and ambiguous annotations (e.g. the same mutation being annotated as disease and benign).
Results
We have developed a novel database, MutHTP, which contains information on 183 395 disease-associated and 17 827 neutral mutations in human transmembrane proteins. For each mutation site MutHTP provides a description of its location with respect to the membrane protein topology, structural environment (if available) and functional features. Comprehensive visualization, search, display and download options are available.
Availability and implementation
The database is publicly available at http://www.iitm.ac.in/bioinfo/MutHTP/. The website is implemented using HTML, PHP and javascript and supports recent versions of all major browsers, such as Firefox, Chrome and Opera.
Supplementary information
Supplementary data are available at Bioinformatics online.
Can orthologous proteins differ in terms of their ability to be secreted? To answer this question, we investigated the distribution of signal peptides within the orthologous groups of ...Enterobacterales. Parsimony analysis and sequence comparisons revealed a large number of signal peptide gain and loss events, in which signal peptides emerge or disappear in the course of evolution. Signal peptide losses prevail over gains, an effect which is especially pronounced in the transition from the free-living or commensal to the endosymbiotic lifestyle. The disproportionate decline in the number of signal peptide-containing proteins in endosymbionts cannot be explained by the overall reduction of their genomes. Signal peptides can be gained and lost either by acquisition/elimination of the corresponding N-terminal regions or by gradual accumulation of mutations. The evolutionary dynamics of signal peptides in bacterial proteins represents a powerful mechanism of functional diversification.
Machine learning (ML) has become an essential asset for the life sciences and medicine. We selected 250 articles describing ML applications from 17 journals sampling 26 different fields between 2011 ...and 2016. Independent evaluation by two readers highlighted three results. First, only half of the articles shared software, 64% shared data and 81% applied any kind of evaluation. Although crucial for ensuring the validity of ML applications, these aspects were met more by publications in lower-ranked journals. Second, the authors’ scientific backgrounds highly influenced how technical aspects were addressed: reproducibility and computational evaluation methods were more prominent with computational co-authors; experimental proofs more with experimentalists. Third, 73% of the ML applications resulted from interdisciplinary collaborations comprising authors from at least two of the three disciplines: computational sciences, biology, and medicine. The results suggested collaborations between computational and experimental scientists to generate more scientifically sound and impactful work integrating knowledge from both domains. Although scientifically more valid solutions and collaborations involving diverse expertise did not correlate with impact factors, such collaborations provide opportunities to both sides: computational scientists are given access to novel and challenging real-world biological data, increasing the scientific impact of their research, and experimentalists benefit from more in-depth computational analyses improving the technical correctness of work.Applications of machine learning in the life sciences and medicine require expertise in computational methods and in scientific subject matter. The authors surveyed articles in the life sciences that included machine learning applications, and found that interdisciplinary collaborations increased the scientific validity of published research.