Interrogating domain-domain interactions with parsimony based approaches

<p>Abstract</p> <p>Background</p> <p>The identification and characterization of interacting domain pairs is an important step towards understanding protein interactions. In the last few years, several methods to predict domain interactions have been proposed. Understanding the power and the limitations of these methods is key to the development of improved approaches and better understanding of the nature of these interactions.</p> <p>Results</p> <p>Building on the previously published Parsimonious Explanation method (PE) to predict domain-domain interactions, we introduced a new Generalized Parsimonious Explanation (GPE) method, which (i) adjusts the granularity of the domain definition to the granularity of the input data set and (ii) permits domain interactions to have different costs. This allowed for preferential selection of the so-called "co-occurring domains" as possible mediators of interactions between proteins. The performance of both variants of the parsimony method are competitive to the performance of the top algorithms for this problem even though parsimony methods use less information than some of the other methods. We also examined possible enrichment of co-occurring domains and homo-domains among domain interactions mediating the interaction of proteins in the network. The corresponding study was performed by surveying domain interactions predicted by the GPE method as well as by using a combinatorial counting approach independent of any prediction method. Our findings indicate that, while there is a considerable propensity towards these special domain pairs among predicted domain interactions, this overrepresentation is significantly lower than in the iPfam dataset.</p> <p>Conclusion</p> <p>The Generalized Parsimonious Explanation approach provides a new means to predict and study domain-domain interactions. We showed that, under the assumption that all protein interactions in the network are mediated by domain interactions, there exists a significant deviation of the properties of domain interactions mediating interactions in the network from that of iPfam data.</p

DOMINE: a comprehensive collection of known and predicted domain-domain interactions

DOMINE is a comprehensive collection of known and predicted domain–domain interactions (DDIs) compiled from 15 different sources. The updated DOMINE includes 2285 new domain–domain interactions (DDIs) inferred from experimentally characterized high-resolution three-dimensional structures, and about 3500 novel predictions by five computational approaches published over the last 3 years. These additions bring the total number of unique DDIs in the updated version to 26 219 among 5140 unique Pfam domains, a 23% increase compared to 20 513 unique DDIs among 4346 unique domains in the previous version. The updated version now contains 6634 known DDIs, and features a new classification scheme to assign confidence levels to predicted DDIs. DOMINE will serve as a valuable resource to those studying protein and domain interactions. Most importantly, DOMINE will not only serve as an excellent reference to bench scientists testing for new interactions but also to bioinformaticans seeking to predict novel protein–protein interactions based on the DDIs. The contents of the DOMINE are available at http://domine.utdallas.edu

Predicting domain-domain interactions using a parsimony approach

We propose a novel approach to predict domain-domain interactions from a protein-protein interaction network. In our method we apply a parsimony-driven explanation of the network, where the domain interactions are inferred using linear programming optimization, and false positives in the protein network are handled by a probabilistic construction. This method outperforms previous approaches by a considerable margin. The results indicate that the parsimony principle provides a correct approach for detecting domain-domain contacts

A Top-Down Approach to Infer and Compare Domain-Domain Interactions across Eight Model Organisms

Knowledge of specific domain-domain interactions (DDIs) is essential to understand the functional significance of protein interaction networks. Despite the availability of an enormous amount of data on protein-protein interactions (PPIs), very little is known about specific DDIs occurring in them. Here, we present a top-down approach to accurately infer functionally relevant DDIs from PPI data. We created a comprehensive, non-redundant dataset of 209,165 experimentally-derived PPIs by combining datasets from five major interaction databases. We introduced an integrated scoring system that uses a novel combination of a set of five orthogonal scoring features covering the probabilistic, evolutionary, evidence-based, spatial and functional properties of interacting domains, which can map the interacting propensity of two domains in many dimensions. This method outperforms similar existing methods both in the accuracy of prediction and in the coverage of domain interaction space. We predicted a set of 52,492 high-confidence DDIs to carry out cross-species comparison of DDI conservation in eight model species including human, mouse, Drosophila, C. elegans, yeast, Plasmodium, E. coli and Arabidopsis. Our results show that only 23% of these DDIs are conserved in at least two species and only 3.8% in at least 4 species, indicating a rather low conservation across species. Pair-wise analysis of DDI conservation revealed a ‘sliding conservation’ pattern between the evolutionarily neighboring species. Our methodology and the high-confidence DDI predictions generated in this study can help to better understand the functional significance of PPIs at the modular level, thus can significantly impact further experimental investigations in systems biology research

InSite: a computational method for identifying protein-protein interaction binding sites on a proteome-wide scale

InSite is a computational method that integrates high-throughput protein and sequence data to infer the specific binding regions of interacting protein pairs

Critical assessment of sequence-based protein-protein interaction prediction methods that do not require homologous protein sequences

<p>Abstract</p> <p>Background</p> <p>Protein-protein interactions underlie many important biological processes. Computational prediction methods can nicely complement experimental approaches for identifying protein-protein interactions. Recently, a unique category of sequence-based prediction methods has been put forward - unique in the sense that it does not require homologous protein sequences. This enables it to be universally applicable to all protein sequences unlike many of previous sequence-based prediction methods. If effective as claimed, these new sequence-based, universally applicable prediction methods would have far-reaching utilities in many areas of biology research.</p> <p>Results</p> <p>Upon close survey, I realized that many of these new methods were ill-tested. In addition, newer methods were often published without performance comparison with previous ones. Thus, it is not clear how good they are and whether there are significant performance differences among them. In this study, I have implemented and thoroughly tested 4 different methods on large-scale, non-redundant data sets. It reveals several important points. First, significant performance differences are noted among different methods. Second, data sets typically used for training prediction methods appear significantly biased, limiting the general applicability of prediction methods trained with them. Third, there is still ample room for further developments. In addition, my analysis illustrates the importance of complementary performance measures coupled with right-sized data sets for meaningful benchmark tests.</p> <p>Conclusions</p> <p>The current study reveals the potentials and limits of the new category of sequence-based protein-protein interaction prediction methods, which in turn provides a firm ground for future endeavours in this important area of contemporary bioinformatics.</p

Organization of Physical Interactomes as Uncovered by Network Schemas

Large-scale protein-protein interaction networks provide new opportunities for understanding cellular organization and functioning. We introduce network schemas to elucidate shared mechanisms within interactomes. Network schemas specify descriptions of proteins and the topology of interactions among them. We develop algorithms for systematically uncovering recurring, over-represented schemas in physical interaction networks. We apply our methods to the S. cerevisiae interactome, focusing on schemas consisting of proteins described via sequence motifs and molecular function annotations and interacting with one another in one of four basic network topologies. We identify hundreds of recurring and over-represented network schemas of various complexity, and demonstrate via graph-theoretic representations how more complex schemas are organized in terms of their lower-order constituents. The uncovered schemas span a wide range of cellular activities, with many signaling and transport related higher-order schemas. We establish the functional importance of the schemas by showing that they correspond to functionally cohesive sets of proteins, are enriched in the frequency with which they have instances in the H. sapiens interactome, and are useful for predicting protein function. Our findings suggest that network schemas are a powerful paradigm for organizing, interrogating, and annotating cellular networks

Contextual Specificity in Peptide-Mediated Protein Interactions

Most biological processes are regulated through complex networks of transient protein interactions where a globular domain in one protein recognizes a linear peptide from another, creating a relatively small contact interface. Although sufficient to ensure binding, these linear motifs alone are usually too short to achieve the high specificity observed, and additional contacts are often encoded in the residues surrounding the motif (i.e. the context). Here, we systematically identified all instances of peptide-mediated protein interactions of known three-dimensional structure and used them to investigate the individual contribution of motif and context to the global binding energy. We found that, on average, the context is responsible for roughly 20% of the binding and plays a crucial role in determining interaction specificity, by either improving the affinity with the native partner or impeding non-native interactions. We also studied and quantified the topological and energetic variability of interaction interfaces, finding a much higher heterogeneity in the context residues than in the consensus binding motifs. Our analysis partially reveals the molecular mechanisms responsible for the dynamic nature of peptide-mediated interactions, and suggests a global evolutionary mechanism to maximise the binding specificity. Finally, we investigated the viability of non-native interactions and highlight cases of potential cross-reaction that might compensate for individual protein failure and establish backup circuits to increase the robustness of cell networks

One Explanation Does Not Fit All The Promise of Interactive Explanations for Machine Learning Transparency

The need for transparency of predictive systems based on Machine Learning algorithms arises as a consequence of their ever-increasing proliferation in the industry. Whenever black-box algorithmic predictions influence human affairs, the inner workings of these algorithms should be scrutinised and their decisions explained to the relevant stakeholders, including the system engineers, the system's operators and the individuals whose case is being decided. While a variety of interpretability and explainability methods is available, none of them is a panacea that can satisfy all diverse expectations and competing objectives that might be required by the parties involved. We address this challenge in this paper by discussing the promises of Interactive Machine Learning for improved transparency of black-box systems using the example of contrastive explanations -- a state-of-the-art approach to Interpretable Machine Learning. Specifically, we show how to personalise counterfactual explanations by interactively adjusting their conditional statements and extract additional explanations by asking follow-up "What if?" questions. Our experience in building, deploying and presenting this type of system allowed us to list desired properties as well as potential limitations, which can be used to guide the development of interactive explainers. While customising the medium of interaction, i.e., the user interface comprising of various communication channels, may give an impression of personalisation, we argue that adjusting the explanation itself and its content is more important. To this end, properties such as breadth, scope, context, purpose and target of the explanation have to be considered, in addition to explicitly informing the explainee about its limitations and caveats...Comment: Published in the Kunstliche Intelligenz journal, special issue on Challenges in Interactive Machine Learnin

Mining Protein-Protein Interactions at Domain and Residue Levels by Machine Learning Methods

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