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Intrinsic disorder predictors were evaluated in several studies including the two large CAID experiments. However, these studies are biased towards eukaryotic proteins and focus primarily on the residue-level predictions. We provide first-of-its-kind assessment that comprehensively covers the taxonomy and evaluates predictions at the residue and disordered region levels. We curate a benchmark dataset that uniformly covers eukaryotic, archaeal, bacterial, and viral proteins. We find that predictive performance differs substantially across taxonomy, where viruses are predicted most accurately, followed by protists and higher eukaryotes, while bacterial and archaeal proteins suffer lower levels of accuracy. These trends are consistent across predictors. We also find that current tools, except for flDPnn, struggle with reproducing native distributions of the numbers and sizes of the disordered regions. Moreover, analysis of two variants of disorder predictions derived from the AlphaFold2 predicted structures reveals that they produce accurate residue-level propensities for archaea, bacteria and protists. However, they underperform for higher eukaryotes and generally struggle to accurately identify disordered regions. Our results motivate development of new predictors that target bacteria and archaea and which produce accurate results at both residue and region levels. We also stress the need to include the region-level assessments in future assessments.
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Disordered linkers (DLs) are intrinsically disordered regions that facilitate movement between adjacent functional regions/domains, contributing to many key cellular functions. The recently completed second Critical Assessments of protein Intrinsic Disorder prediction (CAID2) experiment evaluated DL predictions by considering a rather narrow scenario when predicting 40 proteins that are already known to have DLs. We expand this evaluation by using a much larger set of nearly 350 test proteins from CAID2 and by investigating three distinct scenarios: (1) prediction residues in DLs vs. in non-DL regions (typical use of DL predictors); (2) prediction of residues in DLs vs. other disordered residues (to evaluate whether predictors can differentiate residues in DLs from other types of intrinsically disordered residues); and (3) prediction of proteins harboring DLs. We find that several methods provide relatively accurate predictions of DLs in the first scenario. However, only one method, APOD, accurately identifies DLs among other types of disordered residues (scenario 2) and predicts proteins harboring DLs (scenario 3). We also find that APOD's predictive performance is modest, motivating further research into the development of new and more accurate DL predictors. We note that these efforts will benefit from a growing amount of training data and the availability of sophisticated deep network models and emphasize that future methods should provide accurate results across the three scenarios.
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Biología Computacional , Proteínas Intrínsecamente Desordenadas , Biología Computacional/métodos , Proteínas/química , Proteínas Intrínsecamente Desordenadas/química , Bases de Datos de ProteínasRESUMEN
The DescribePROT database of amino acid-level descriptors of protein structures and functions was substantially expanded since its release in 2020. This expansion includes substantial increase in the size, scope, and quality of the underlying data, the addition of experimental structural information, the inclusion of new data download options, and an upgraded graphical interface. DescribePROT currently covers 19 structural and functional descriptors for proteins in 273 reference proteomes generated by 11 accurate and complementary predictive tools. Users can search our resource in multiple ways, interact with the data using the graphical interface, and download data at various scales including individual proteins, entire proteomes, and whole database. The annotations in DescribePROT are useful for a broad spectrum of studies that include investigations of protein structure and function, development and validation of predictive tools, and to support efforts in understanding molecular underpinnings of diseases and development of therapeutics. DescribePROT can be freely accessed at http://biomine.cs.vcu.edu/servers/DESCRIBEPROT/.
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Aminoácidos , Proteoma , Proteoma/química , Bases de Datos FactualesRESUMEN
Current predictors of DNA-binding residues (DBRs) from protein sequences belong to two distinct groups, those trained on binding annotations extracted from structured protein-DNA complexes (structure-trained) vs. intrinsically disordered proteins (disorder-trained). We complete the first empirical analysis of predictive performance across the structure- and disorder-annotated proteins for a representative collection of ten predictors. Majority of the structure-trained tools perform well on the structure-annotated proteins while doing relatively poorly on the disorder-annotated proteins, and vice versa. Several methods make accurate predictions for the structure-annotated proteins or the disorder-annotated proteins, but none performs highly accurately for both annotation types. Moreover, most predictors make excessive cross-predictions for the disorder-annotated proteins, where residues that interact with non-DNA ligand types are predicted as DBRs. Motivated by these results, we design, validate and deploy an innovative meta-model, hybridDBRpred, that uses deep transformer network to combine predictions generated by three best current predictors. HybridDBRpred provides accurate predictions and low levels of cross-predictions across the two annotation types, and is statistically more accurate than each of the ten tools and baseline meta-predictors that rely on averaging and logistic regression. We deploy hybridDBRpred as a convenient web server at http://biomine.cs.vcu.edu/servers/hybridDBRpred/ and provide the corresponding source code at https://github.com/jianzhang-xynu/hybridDBRpred.
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Proteínas de Unión al ADN , Programas Informáticos , Secuencia de Aminoácidos , Aminoácidos , Biología Computacional/métodos , Bases de Datos de Proteínas , ADN , Proteínas Intrínsecamente Desordenadas/química , Proteínas de Unión al ADN/químicaRESUMEN
Motivation: Development of bioinformatics methods is a long, complex and resource-hungry process. Hundreds of these tools were released. While some methods are highly cited and used, many suffer relatively low citation rates. We empirically analyze a large collection of recently released methods in three diverse protein function and disorder prediction areas to identify key factors that contribute to increased citations. Results: We show that provision of a working web server significantly boosts citation rates. On average, methods with working web servers generate three times as many citations compared to tools that are available as only source code, have no code and no server, or are no longer available. This observation holds consistently across different research areas and publication years. We also find that differences in predictive performance are unlikely to impact citation rates. Overall, our empirical results suggest that a relatively low-cost investment into the provision and long-term support of web servers would substantially increase the impact of bioinformatics tools.
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Proteases contribute to a broad spectrum of cellular functions. Given a relatively limited amount of experimental data, developing accurate sequence-based predictors of substrate cleavage sites facilitates a better understanding of protease functions and substrate specificity. While many protease-specific predictors of substrate cleavage sites were developed, these efforts are outpaced by the growth of the protease substrate cleavage data. In particular, since data for 100+ protease types are available and this number continues to grow, it becomes impractical to publish predictors for new protease types, and instead it might be better to provide a computational platform that helps users to quickly and efficiently build predictors that address their specific needs. To this end, we conceptualized, developed, tested and released a versatile bioinformatics platform, ProsperousPlus, that empowers users, even those with no programming or little bioinformatics background, to build fast and accurate predictors of substrate cleavage sites. ProsperousPlus facilitates the use of the rapidly accumulating substrate cleavage data to train, empirically assess and deploy predictive models for user-selected substrate types. Benchmarking tests on test datasets show that our platform produces predictors that on average exceed the predictive performance of current state-of-the-art approaches. ProsperousPlus is available as a webserver and a stand-alone software package at http://prosperousplus.unimelb-biotools.cloud.edu.au/.
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Aprendizaje Automático , Péptido Hidrolasas , Péptido Hidrolasas/metabolismo , Especificidad por Sustrato , AlgoritmosRESUMEN
Intrinsic disorder is instrumental for a wide range of protein functions, and its analysis, using computational predictions from primary structures, complements secondary and tertiary structure-based approaches. In this Tutorial, we provide an overview and comparison of 23 publicly available computational tools with complementary parameters useful for intrinsic disorder prediction, partly relying on results from the Critical Assessment of protein Intrinsic Disorder prediction experiment. We consider factors such as accuracy, runtime, availability and the need for functional insights. The selected tools are available as web servers and downloadable programs, offer state-of-the-art predictions and can be used in a high-throughput manner. We provide examples and instructions for the selected tools to illustrate practical aspects related to the submission, collection and interpretation of predictions, as well as the timing and their limitations. We highlight two predictors for intrinsically disordered proteins, flDPnn as accurate and fast and IUPred as very fast and moderately accurate, while suggesting ANCHOR2 and MoRFchibi as two of the best-performing predictors for intrinsically disordered region binding. We link these tools to additional resources, including databases of predictions and web servers that integrate multiple predictive methods. Altogether, this Tutorial provides a hands-on guide to comparatively evaluating multiple predictors, submitting and collecting their own predictions, and reading and interpreting results. It is suitable for experimentalists and computational biologists interested in accurately and conveniently identifying intrinsic disorder, facilitating the functional characterization of the rapidly growing collections of protein sequences.
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Biología Computacional , Proteínas Intrínsecamente Desordenadas , Biología Computacional/métodos , Bases de Datos de Proteínas , Proteínas Intrínsecamente Desordenadas/química , Secuencia de AminoácidosRESUMEN
Molecular recognition features (MoRFs) are a commonly occurring type of intrinsically disordered regions (IDRs) that undergo disorder-to-order transition upon binding to partner molecules. We focus on recently characterized and functionally important membrane-binding MoRFs (MemMoRFs). Motivated by the lack of computational tools that predict MemMoRFs, we use a dataset of experimentally annotated MemMoRFs to conceptualize, design, evaluate and release an accurate sequence-based predictor. We rely on state-of-the-art tools that predict residues that possess key characteristics of MemMoRFs, such as intrinsic disorder, disorder-to-order transition and lipid-binding. We identify and combine results from three tools that include flDPnn for the disorder prediction, DisoLipPred for the prediction of disordered lipid-binding regions, and MoRFCHiBiLight for the prediction of disorder-to-order transitioning protein binding regions. Our empirical analysis demonstrates that combining results produced by these three methods generates accurate predictions of MemMoRFs. We also show that use of a smoothing operator produces predictions that closely mimic the number and sizes of the native MemMoRF regions. The resulting CoMemMoRFPred method is available as an easy-to-use webserver at http://biomine.cs.vcu.edu/servers/CoMemMoRFPred. This tool will aid future studies of MemMoRFs in the context of exploring their abundance, cellular functions, and roles in pathologic phenomena.
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There are over 100 computational predictors of intrinsic disorder. These methods predict amino acid-level propensities for disorder directly from protein sequences. The propensities can be used to annotate putative disordered residues and regions. This unit provides a practical and holistic introduction to the sequence-based intrinsic disorder prediction. We define intrinsic disorder, explain the format of computational prediction of disorder, and identify and describe several accurate predictors. We also introduce recently released databases of intrinsic disorder predictions and use an illustrative example to provide insights into how predictions should be interpreted and combined. Lastly, we summarize key experimental methods that can be used to validate computational predictions. © 2023 Wiley Periodicals LLC.
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Aminoácidos , Secuencia de Aminoácidos , Bases de Datos Factuales , Proyectos de InvestigaciónRESUMEN
Intrinsic disorder in proteins is relatively abundant in nature and essential for a broad spectrum of cellular functions. While disorder can be accurately predicted from protein sequences, as it was empirically demonstrated in recent community-organized assessments, it is rather challenging to collect and compile a comprehensive prediction that covers multiple disorder functions. To this end, we introduce the DEPICTER2 (DisorderEd PredictIon CenTER) webserver that offers convenient access to a curated collection of fast and accurate disorder and disorder function predictors. This server includes a state-of-the-art disorder predictor, flDPnn, and five modern methods that cover all currently predictable disorder functions: disordered linkers and protein, peptide, DNA, RNA and lipid binding. DEPICTER2 allows selection of any combination of the six methods, batch predictions of up to 25 proteins per request and provides interactive visualization of the resulting predictions. The webserver is freely available at http://biomine.cs.vcu.edu/servers/DEPICTER2/.
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Biología Computacional , Visualización de Datos , Internet , Proteínas , Biología Computacional/instrumentación , Biología Computacional/métodos , Bases de Datos de Proteínas , Proteínas/química , Proteínas/genética , Proteínas/metabolismo , Unión Proteica , Interfaz Usuario-ComputadorRESUMEN
Human leukocyte antigen class I (HLA-I) molecules bind intracellular peptides produced by protein hydrolysis and present them to the T cells for immune recognition and response. Prediction of peptides that bind HLA-I molecules is very important in immunotherapy. A growing number of computational predictors have been developed in recent years. We survey a comprehensive collection of 27 tools focusing on their input and output data characteristics, key aspects of the underlying predictive models and their availability. Moreover, we evaluate predictive performance for eight representative predictors. We consider a wide spectrum of relevant aspects including allele-specific analysis, influence of negative to positive data ratios and runtime. We also curate high-quality benchmark datasets based on analysis of the consistency of the data labels. Results reveal that each considered method provides accurate results, which can be explained by our analysis that finds that their predictive models capture meaningful binding motifs. Although some methods are overall more accurate than others, we find that none of them is universally superior. We provide a comprehensive comparison of the convenience as well as the accuracy of the methods under specific prediction scenarios, such as for specific alleles, metrics of predictive performance and constraints on runtime. Our systematic and broad analysis provides informative clues to the users to identify the most suitable tools for a given prediction scenario and for the developers to design future methods.
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Antígenos de Histocompatibilidad Clase I , Péptidos , Humanos , Unión Proteica , Péptidos/químicaRESUMEN
One of the key features of intrinsically disordered regions (IDRs) is their ability to interact with a broad range of partner molecules. Multiple types of interacting IDRs were identified including molecular recognition fragments (MoRFs), short linear sequence motifs (SLiMs), and protein-, nucleic acids- and lipid-binding regions. Prediction of binding IDRs in protein sequences is gaining momentum in recent years. We survey 38 predictors of binding IDRs that target interactions with a diverse set of partners, such as peptides, proteins, RNA, DNA and lipids. We offer a historical perspective and highlight key events that fueled efforts to develop these methods. These tools rely on a diverse range of predictive architectures that include scoring functions, regular expressions, traditional and deep machine learning and meta-models. Recent efforts focus on the development of deep neural network-based architectures and extending coverage to RNA, DNA and lipid-binding IDRs. We analyze availability of these methods and show that providing implementations and webservers results in much higher rates of citations/use. We also make several recommendations to take advantage of modern deep network architectures, develop tools that bundle predictions of multiple and different types of binding IDRs, and work on algorithms that model structures of the resulting complexes.
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The sequence-based predictors of RNA-binding residues (RBRs) are trained on either structure-annotated or disorder-annotated binding regions. A recent study of predictors of protein-binding residues shows that they are plagued by high levels of cross-predictions (protein binding residues are predicted as nucleic acid binding) and that structure-trained predictors perform poorly for the disorder-annotated regions and vice versa. Consequently, we analyze a representative set of the structure and disorder trained predictors of RBRs to comprehensively assess quality of their predictions. Our empirical analysis that relies on a new and low-similarity benchmark dataset reveals that the structure-trained predictors of RBRs perform well for the structure-annotated proteins while the disorder-trained predictors provide accurate results for the disorder-annotated proteins. However, these methods work only modestly well on the opposite types of annotations, motivating the need for new solutions. Using an empirical approach, we design HybridRNAbind meta-model that generates accurate predictions and low amounts of cross-predictions when tested on data that combines structure and disorder-annotated RBRs. We release this meta-model as a convenient webserver which is available at https://www.csuligroup.com/hybridRNAbind/.
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Proteínas , Proteínas de Unión al ARN , ARN , Biología Computacional/métodos , Bases de Datos de Proteínas , Unión Proteica/genética , Proteínas/química , ARN/química , Proteínas de Unión al ARN/químicaRESUMEN
Current sequence-based predictors of protein-binding residues (PBRs) belong to two distinct categories: structure-trained vs. intrinsic disorder-trained. Since disordered PBRs differ from structured PBRs in several ways, including ability to bind multiple partners by folding into different conformations and enrichment in different amino acids, the structure-trained and disorder-trained predictors were shown to provide inaccurate results for the other annotation type. A simple consensus-based solution that combines structure- and disorder-trained methods provides limited levels of predictive performance and generates relatively many cross-predictions, where residues that interact with other ligand types are predicted as PBRs. We address this unsolved problem by designing a novel and fast deep-learner, DeepPRObind, that relies on carefully designed modular convolutional architecture and uses innovative aggregate input features. Comparative empirical tests on a low-similarity test dataset reveal that DeepPRObind generates accurate predictions of structured and disordered PBRs and low amounts of cross-predictions, outperforming a comprehensive collection of 12 predictors of PBRs. Given the relatively low runtime of DeepPRObind (40 seconds per protein), we further validate its results based on an analysis of putative PBRs in the yeast proteome, confirming that interactions in disordered regions are enriched among hub proteins. We release DeepPRObind as a convenient web server at https://www.csuligroup.com/DeepPRObind/.
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Aminoácidos , Biología Computacional , Aprendizaje Profundo , Unión Proteica , Biología Computacional/métodos , Bases de Datos de Proteínas , Proteoma/química , Conformación ProteicaRESUMEN
One of key features of intrinsically disordered regions (IDRs) is facilitation of protein-protein and protein-nucleic acids interactions. These disordered binding regions include molecular recognition features (MoRFs), short linear motifs (SLiMs) and longer binding domains. Vast majority of current predictors of disordered binding regions target MoRFs, with a handful of methods that predict SLiMs and disordered protein-binding domains. A new and broader class of disordered binding regions, linear interacting peptides (LIPs), was introduced recently and applied in the MobiDB resource. LIPs are segments in protein sequences that undergo disorder-to-order transition upon binding to a protein or a nucleic acid, and they cover MoRFs, SLiMs and disordered protein-binding domains. Although current predictors of MoRFs and disordered protein-binding regions could be used to identify some LIPs, there are no dedicated sequence-based predictors of LIPs. To this end, we introduce CLIP, a new predictor of LIPs that utilizes robust logistic regression model to combine three complementary types of inputs: co-evolutionary information derived from multiple sequence alignments, physicochemical profiles and disorder predictions. Ablation analysis suggests that the co-evolutionary information is particularly useful for this prediction and that combining the three inputs provides substantial improvements when compared to using these inputs individually. Comparative empirical assessments using low-similarity test datasets reveal that CLIP secures area under receiver operating characteristic curve (AUC) of 0.8 and substantially improves over the results produced by the closest current tools that predict MoRFs and disordered protein-binding regions. The webserver of CLIP is freely available at http://biomine.cs.vcu.edu/servers/CLIP/ and the standalone code can be downloaded from http://yanglab.qd.sdu.edu.cn/download/CLIP/.
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Proteínas Intrínsecamente Desordenadas , Proteínas Intrínsecamente Desordenadas/química , Biología Computacional/métodos , Secuencia de Aminoácidos , Péptidos/metabolismo , Dominios Proteicos , Bases de Datos de Proteínas , Unión ProteicaRESUMEN
Protein sequence-based predictors of nucleic acid (NA)-binding include methods that predict NA-binding proteins and NA-binding residues. The residue-level tools produce more details but suffer high computational cost since they must predict every amino acid in the input sequence and rely on multiple sequence alignments. We propose an alternative approach that predicts content (fraction) of the NA-binding residues, offering more information than the protein-level prediction and much shorter runtime than the residue-level tools. Our first-of-its-kind content predictor, qNABpredict, relies on a small, rationally designed and fast-to-compute feature set that represents relevant characteristics extracted from the input sequence and a well-parametrized support vector regression model. We provide two versions of qNABpredict, a taxonomy-agnostic model that can be used for proteins of unknown taxonomic origin and more accurate taxonomy-aware models that are tailored to specific taxonomic kingdoms: archaea, bacteria, eukaryota, and viruses. Empirical tests on a low-similarity test dataset show that qNABpredict is 100 times faster and generates statistically more accurate content predictions when compared to the content extracted from results produced by the residue-level predictors. We also show that qNABpredict's content predictions can be used to improve results generated by the residue-level predictors. We release qNABpredict as a convenient webserver and source code at http://biomine.cs.vcu.edu/servers/qNABpredict/. This new tool should be particularly useful to predict details of protein-NA interactions for large protein families and proteomes.
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Aminoácidos , Ácidos Nucleicos , Bases de Datos de Proteínas , Secuencia de Aminoácidos , Proteoma , Biología Computacional/métodosRESUMEN
We expand studies of AlphaFold2 (AF2) in the context of intrinsic disorder prediction by comparing it against a broad selection of 20 accurate, popular and recently released disorder predictors. We use 25% larger benchmark dataset with 646 proteins and cover protein-level predictions of disorder content and fully disordered proteins. AF2-based disorder predictions secure a relatively high Area Under receiver operating characteristic Curve (AUC) of 0.77 and are statistically outperformed by several modern disorder predictors that secure AUCs around 0.8 with median runtime of about 20 s compared to 1200 s for AF2. Moreover, AF2 provides modestly accurate predictions of fully disordered proteins (F1 = 0.59 vs. 0.91 for the best disorder predictor) and disorder content (mean absolute error of 0.21 vs. 0.15). AF2 also generates statistically more accurate disorder predictions for about 20% of proteins that have relatively short sequences and a few disordered regions that tend to be located at the sequence termini, and which are absent of disordered protein-binding regions. Interestingly, AF2 and the most accurate disorder predictors rely on deep neural networks, suggesting that these models are useful for protein structure and disorder predictions.
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SARS-CoV-2 is the infectious agent responsible for the coronavirus disease since 2019, which is the viral pneumonia pandemic worldwide. The structural knowledge on SARS-CoV-2 is rather limited. These limitations are also applicable to one of the most attractive drug targets of SARS-CoV-2 proteins - namely, main protease Mpro, also known as 3C-like protease (3CLpro). This protein is crucial for the processing of the viral polyproteins and plays crucial roles in interfering viral replication and transcription. In fact, although the crystal structure of this protein with an inhibitor was solved, Mpro conformational dynamics in aqueous solution is usually studied by molecular dynamics simulations without special sampling techniques. We conducted replica exchange molecular dynamics simulations on Mpro in water and report the dynamic structures of Mpro in an aqueous environment including root mean square fluctuations, secondary structure properties, radius of gyration, and end-to-end distances, chemical shift values, intrinsic disorder characteristics of Mpro and its active sites with a set of computational tools. The active sites we found coincide with the currently known sites and include a new interface for interaction with a protein partner.
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Intrinsically disordered regions (IDRs) carry out many cellular functions and vary in length and placement in protein sequences. This diversity leads to variations in the underlying compositional biases, which were demonstrated for the short vs. long IDRs. We analyze compositional biases across four classes of disorder: fully disordered proteins; short IDRs; long IDRs; and binding IDRs. We identify three distinct biases: for the fully disordered proteins, the short IDRs and the long and binding IDRs combined. We also investigate compositional bias for putative disorder produced by leading disorder predictors and find that it is similar to the bias of the native disorder. Interestingly, the accuracy of disorder predictions across different methods is correlated with the correctness of the compositional bias of their predictions highlighting the importance of the compositional bias. The predictive quality is relatively low for the disorder classes with compositional bias that is the most different from the "generic" disorder bias, while being much higher for the classes with the most similar bias. We discover that different predictors perform best across different classes of disorder. This suggests that no single predictor is universally best and motivates the development of new architectures that combine models that target specific disorder classes.
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Proteínas Intrínsecamente Desordenadas , Secuencia de Aminoácidos , Sesgo , Proteínas Intrínsecamente Desordenadas/metabolismo , Conformación ProteicaRESUMEN
Sequence-based predictors of the residue-level protein function and structure cover a broad spectrum of characteristics including intrinsic disorder, secondary structure, solvent accessibility and binding to nucleic acids. They were catalogued and evaluated in numerous surveys and assessments. However, methods focusing on a given characteristic are studied separately from predictors of other characteristics, while they are typically used on the same proteins. We fill this void by studying complementarity of a representative collection of methods that target different predictions using a large, taxonomically consistent, and low similarity dataset of human proteins. First, we bridge the gap between the communities that develop structure-trained vs. disorder-trained predictors of binding residues. Motivated by a recent study of the protein-binding residue predictions, we empirically find that combining the structure-trained and disorder-trained predictors of the DNA-binding and RNA-binding residues leads to substantial improvements in predictive quality. Second, we investigate whether diverse predictors generate results that accurately reproduce relations between secondary structure, solvent accessibility, interaction sites, and intrinsic disorder that are present in the experimental data. Our empirical analysis concludes that predictions accurately reflect all combinations of these relations. Altogether, this study provides unique insights that support combining results produced by diverse residue-level predictors of protein function and structure.