Methods for protein complex prediction and their contributions towards understanding the organization, function and dynamics of complexes

Complexes of physically interacting proteins constitute fundamental functional units responsible for driving biological processes within cells. A faithful reconstruction of the entire set of complexes is therefore essential to understand the functional organization of cells. In this review, we discuss the key contributions of computational methods developed till date (approximately between 2003 and 2015) for identifying complexes from the network of interacting proteins (PPI network). We evaluate in depth the performance of these methods on PPI datasets from yeast, and highlight challenges faced by these methods, in particular detection of sparse and small or sub- complexes and discerning of overlapping complexes. We describe methods for integrating diverse information including expression profiles and 3D structures of proteins with PPI networks to understand the dynamics of complex formation, for instance, of time-based assembly of complex subunits and formation of fuzzy complexes from intrinsically disordered proteins. Finally, we discuss methods for identifying dysfunctional complexes in human diseases, an application that is proving invaluable to understand disease mechanisms and to discover novel therapeutic targets. We hope this review aptly commemorates a decade of research on computational prediction of complexes and constitutes a valuable reference for further advancements in this exciting area.Comment: 1 Tabl

Unsupervised Learning and Multipartite Network Models: A Promising Approach for Understanding Traditional Medicine

The ultimate goal of precision medicine is to determine right treatment for right patients based on precise diagnosis. To achieve this goal, correct stratification of patients using molecular features and clinical phenotypes is crucial. During the long history of medical science, our understanding on disease classification has been improved greatly by chemistry and molecular biology. Nowadays, we gain access to large scale patient-derived data by high-throughput technologies, generating a greater need for data science including unsupervised learning and network modeling. Unsupervised learning methods such as clustering could be a better solution to stratify patients when there is a lack of predefined classifiers. In network modularity analysis, clustering methods can be also applied to elucidate the complex structure of biological and disease networks at the systems level. In this review, we went over the main points of clustering analysis and network modeling, particularly in the context of Traditional Chinese medicine (TCM). We showed that this approach can provide novel insights on the rationale of classification for TCM herbs. In a case study, using a modularity analysis of multipartite networks, we illustrated that the TCM classifications are associated with the chemical properties of the herb ingredients. We concluded that multipartite network modeling may become a suitable data integration tool for understanding the mechanisms of actions of traditional medicine.Peer reviewe

A Comparative Study of Pairwise Learning Methods based on Kernel Ridge Regression

Many machine learning problems can be formulated as predicting labels for a pair of objects. Problems of that kind are often referred to as pairwise learning, dyadic prediction or network inference problems. During the last decade kernel methods have played a dominant role in pairwise learning. They still obtain a state-of-the-art predictive performance, but a theoretical analysis of their behavior has been underexplored in the machine learning literature. In this work we review and unify existing kernel-based algorithms that are commonly used in different pairwise learning settings, ranging from matrix filtering to zero-shot learning. To this end, we focus on closed-form efficient instantiations of Kronecker kernel ridge regression. We show that independent task kernel ridge regression, two-step kernel ridge regression and a linear matrix filter arise naturally as a special case of Kronecker kernel ridge regression, implying that all these methods implicitly minimize a squared loss. In addition, we analyze universality, consistency and spectral filtering properties. Our theoretical results provide valuable insights in assessing the advantages and limitations of existing pairwise learning methods.Comment: arXiv admin note: text overlap with arXiv:1606.0427

Multi-faceted Structure-Activity Relationship Analysis Using Graphical Representations

A core focus in medicinal chemistry is the interpretation of structure-activity relationships (SARs) of small molecules. SAR analysis is typically carried out on a case-by-case basis for compound sets that share activity against a given target. Although SAR investigations are not a priori dependent on computational approaches, limitations imposed by steady rise in activity information have necessitated the use of such methodologies. Moreover, understanding SARs in multi-target space is extremely difficult. Conceptually different computational approaches are reported in this thesis for graphical SAR analysis in single- as well as multi-target space. Activity landscape models are often used to describe the underlying SAR characteristics of compound sets. Theoretical activity landscapes that are reminiscent of topological maps intuitively represent distributions of pair-wise similarity and potency difference information as three-dimensional surfaces. These models provide easy access to identification of various SAR features. Therefore, such landscapes for actual data sets are generated and compared with graph-based representations. Existing graphical data structures are adapted to include mechanism of action information for receptor ligands to facilitate simultaneous SAR and mechanism-related analyses with the objective of identifying structural modifications responsible for switching molecular mechanisms of action. Typically, SAR analysis focuses on systematic pair-wise relationships of compound similarity and potency differences. Therefore, an approach is reported to calculate SAR feature probabilities on the basis of these pair-wise relationships for individual compounds in a ligand set. The consequent expansion of feature categories improves the analysis of local SAR environments. Graphical representations are designed to avoid a dependence on preconceived SAR models. Such representations are suitable for systematic large-scale SAR exploration. Methods for the navigation of SARs in multi-target space using simple and interpretable data structures are introduced. In summary, multi-faceted SAR analysis aided by computational means forms the primary objective of this dissertation

Knowledge extraction from unstructured data

Data availability is becoming more essential, considering the current growth of web-based data. The data available on the web are represented as unstructured, semi-structured, or structured data. In order to make the web-based data available for several Natural Language Processing or Data Mining tasks, the data needs to be presented as machine-readable data in a structured format. Thus, techniques for addressing the problem of capturing knowledge from unstructured data sources are needed. Knowledge extraction methods are used by the research communities to address this problem; methods that are able to capture knowledge in a natural language text and map the extracted knowledge to existing knowledge presented in knowledge graphs (KGs). These knowledge extraction methods include Named-entity recognition, Named-entity Disambiguation, Relation Recognition, and Relation Linking. This thesis addresses the problem of extracting knowledge over unstructured data and discovering patterns in the extracted knowledge. We devise a rule-based approach for entity and relation recognition and linking. The defined approach effectively maps entities and relations within a text to their resources in a target KG. Additionally, it overcomes the challenges of recognizing and linking entities and relations to a specific KG by employing devised catalogs of linguistic and domain-specific rules that state the criteria to recognize entities in a sentence of a particular language, and a deductive database that encodes knowledge in community-maintained KGs. Moreover, we define a Neuro-symbolic approach for the tasks of knowledge extraction in encyclopedic and domain-specific domains; it combines symbolic and sub-symbolic components to overcome the challenges of entity recognition and linking and the limitation of the availability of training data while maintaining the accuracy of recognizing and linking entities. Additionally, we present a context-aware framework for unveiling semantically related posts in a corpus; it is a knowledge-driven framework that retrieves associated posts effectively. We cast the problem of unveiling semantically related posts in a corpus into the Vertex Coloring Problem. We evaluate the performance of our techniques on several benchmarks related to various domains for knowledge extraction tasks. Furthermore, we apply these methods in real-world scenarios from national and international projects. The outcomes show that our techniques are able to effectively extract knowledge encoded in unstructured data and discover patterns over the extracted knowledge presented as machine-readable data. More importantly, the evaluation results provide evidence to the effectiveness of combining the reasoning capacity of the symbolic frameworks with the power of pattern recognition and classification of sub-symbolic models

FuzDB: database of fuzzy complexes, a tool to develop stochastic structure-function relationships for protein complexes and higher-order assemblies

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