SMART: Unique splitting-while-merging framework for gene clustering

Copyright @ 2014 Fa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Successful clustering algorithms are highly dependent on parameter settings. The clustering performance degrades significantly unless parameters are properly set, and yet, it is difficult to set these parameters a priori. To address this issue, in this paper, we propose a unique splitting-while-merging clustering framework, named “splitting merging awareness tactics” (SMART), which does not require any a priori knowledge of either the number of clusters or even the possible range of this number. Unlike existing self-splitting algorithms, which over-cluster the dataset to a large number of clusters and then merge some similar clusters, our framework has the ability to split and merge clusters automatically during the process and produces the the most reliable clustering results, by intrinsically integrating many clustering techniques and tasks. The SMART framework is implemented with two distinct clustering paradigms in two algorithms: competitive learning and finite mixture model. Nevertheless, within the proposed SMART framework, many other algorithms can be derived for different clustering paradigms. The minimum message length algorithm is integrated into the framework as the clustering selection criterion. The usefulness of the SMART framework and its algorithms is tested in demonstration datasets and simulated gene expression datasets. Moreover, two real microarray gene expression datasets are studied using this approach. Based on the performance of many metrics, all numerical results show that SMART is superior to compared existing self-splitting algorithms and traditional algorithms. Three main properties of the proposed SMART framework are summarized as: (1) needing no parameters dependent on the respective dataset or a priori knowledge about the datasets, (2) extendible to many different applications, (3) offering superior performance compared with counterpart algorithms.National Institute for Health Researc

Quantitative and evolutionary global analysis of enzyme reaction mechanisms

The most widely used classification system describing enzyme-catalysed reactions is the Enzyme Commission (EC) number. Understanding enzyme function is important for both fundamental scientific and pharmaceutical reasons. The EC classification is essentially unrelated to the reaction mechanism. In this work we address two important questions related to enzyme function diversity. First, to investigate the relationship between the reaction mechanisms as described in the MACiE (Mechanism, Annotation, and Classification in Enzymes) database and the main top-level class of the EC classification. Second, how well these enzymes biocatalysis are adapted in nature. In this thesis, we have retrieved 335 enzyme reactions from the MACiE database. We consider two ways of encoding the reaction mechanism in descriptors, and three approaches that encode only the overall chemical reaction. To proceed through my work, we first develop a basic model to cluster the enzymatic reactions. Global study of enzyme reaction mechanism may provide important insights for better understanding of the diversity of chemical reactions of enzymes. Clustering analysis in such research is very common practice. Clustering algorithms suffer from various issues, such as requiring determination of the input parameters and stopping criteria, and very often a need to specify the number of clusters in advance. Using several well known metrics, we tried to optimize the clustering outputs for each of the algorithms, with equivocal results that suggested the existence of between two and over a hundred clusters. This motivated us to design and implement our algorithm, PFClust (Parameter-Free Clustering), where no prior information is required to determine the number of cluster. The analysis highlights the structure of the enzyme overall and mechanistic reaction. This suggests that mechanistic similarity can influence approaches for function prediction and automatic annotation of newly discovered protein and gene sequences. We then develop and evaluate the method for enzyme function prediction using machine learning methods. Our results suggest that pairs of similar enzyme reactions tend to proceed by different mechanisms. The machine learning method needs only chemoinformatics descriptors as an input and is applicable for regression analysis. The last phase of this work is to test the evolution of chemical mechanisms mapped onto ancestral enzymes. This domain occurrence and abundance in modern proteins has showed that the / architecture is probably the oldest fold design. These observations have important implications for the origins of biochemistry and for exploring structure-function relationships. Over half of the known mechanisms are introduced before architectural diversification over the evolutionary time. The other halves of the mechanisms are invented gradually over the evolutionary timeline just after organismal diversification. Moreover, many common mechanisms includes fundamental building blocks of enzyme chemistry were found to be associated with the ancestral fold

Computational Investigations of Backbone Dynamics in Intrinsically Disordered Proteins

Intrinsically disordered proteins (IDPs), due to their dynamic nature, play important roles in molecular recognition, signalling, regulation, or binding of nucleic acids. IDPs have been extensively studied computationally in terms of binary disorder/order classification. This approach has proven to be fruitful and enabled researchers to estimate the amount of disorder in prokaryotic and eukaryotic genomes. Other computational methods – molecular dynamics, or other simulation techniques, require a starting structure. However, there are no approaches permitting insight into the behaviour of disordered ensembles from sequence alone. Such a method would facilitate the study of proteins of unknown structures, help to obtain a better classification of the disordered regions, and the design disorder-to-order transitions. In this work, I develop FRAGFOLD-IDP, a method to address this issue. Using a fragment-based structure prediction approach – FRAGFOLD, I generate the ensembles of IDPs and show that the features extracted from them correspond well with the backbone dynamics of NMR ensembles deposited in the PDB. FRAGFOLD-IDP predictions significantly improve over a naïve approach and help to get a better insight into the dynamics of the disordered ensembles. The results also show it is not necessary to predict the correct fold of the protein to reliably assign per-residue fluctuations to the sequence in question. This suggests that disorder is a local property and it does not depend on the protein fold. Next, I validate FRAGFOLD-IDP on the disorder classification task and show that the method performs comparably to machine learning-based approaches designed specifically for this task. I also found that FRAGFOLD-IDP produces results on par with DynaMine, a machine learning approach to predict the NMR order parameters and that the results of both methods are not correlated. Thus, I constructed a consensus neural network predictor, which takes the results of FRAGFOLD-IDP, DynaMine and physicochemical features to predict per-residue fluctuations, improving upon both input methods

Key concepts of group pattern discovery algorithms from spatio-temporal trajectories

Over the years, the increasing development of location acquisition devices have generated a significant amount of spatio-temporal data. This data can be further analysed in search for some interesting patterns, new information, or to construct predictive models such as next location prediction. The goal of this paper is to contribute to the future research and development of group pattern discovery algorithms from spatio-temporal data by providing an insight into algorithms design in this research area which is based on a comprehensive classification of state-of-the-art models. This work includes static, big data as well as data stream processing models which to the best of authors’knowledge is the first attempt of presenting them in this context.Furthermore, the currently available surveys and taxonomies in this research area do not focus on group pattern mining algorithms nor include the state-of-the-art models. The authors conclude with the proposal of a conceptual model of Universal,Streaming, Distributed and Parameter-light (UDSP) algorithm that addresses current challenges in this research area

Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies.

HIGHLIGHTS Many CNS targets are being explored for multi-target drug designNew databases and cheminformatic methods enable prediction of primary pharmaceutical target and off-targets of compoundsQSAR, virtual screening and docking methods increase the potential of rational drug design The diverse cerebral mechanisms implicated in Central Nervous System (CNS) diseases together with the heterogeneous and overlapping nature of phenotypes indicated that multitarget strategies may be appropriate for the improved treatment of complex brain diseases. Understanding how the neurotransmitter systems interact is also important in optimizing therapeutic strategies. Pharmacological intervention on one target will often influence another one, such as the well-established serotonin-dopamine interaction or the dopamine-glutamate interaction. It is now accepted that drug action can involve plural targets and that polypharmacological interaction with multiple targets, to address disease in more subtle and effective ways, is a key concept for development of novel drug candidates against complex CNS diseases. A multi-target therapeutic strategy for Alzheimer's disease resulted in the development of very effective Multi-Target Designed Ligands (MTDL) that act on both the cholinergic and monoaminergic systems, and also retard the progression of neurodegeneration by inhibiting amyloid aggregation. Many compounds already in databases have been investigated as ligands for multiple targets in drug-discovery programs. A probabilistic method, the Parzen-Rosenblatt Window approach, was used to build a "predictor" model using data collected from the ChEMBL database. The model can be used to predict both the primary pharmaceutical target and off-targets of a compound based on its structure. Several multi-target ligands were selected for further study, as compounds with possible additional beneficial pharmacological activities. Based on all these findings, it is concluded that multipotent ligands targeting AChE/MAO-A/MAO-B and also D1-R/D2-R/5-HT2A -R/H3-R are promising novel drug candidates with improved efficacy and beneficial neuroleptic and procognitive activities in treatment of Alzheimer's and related neurodegenerative diseases. Structural information for drug targets permits docking and virtual screening and exploration of the molecular determinants of binding, hence facilitating the design of multi-targeted drugs. The crystal structures and models of enzymes of the monoaminergic and cholinergic systems have been used to investigate the structural origins of target selectivity and to identify molecular determinants, in order to design MTDLs

OptCluster : an R package for determining the optimal clustering algorithm and optimal number of clusters.

Determining the best clustering algorithm and ideal number of clusters for a particular dataset is a fundamental difficulty in unsupervised clustering analysis. In biological research, data generated from Next Generation Sequencing technology and microarray gene expression data are becoming more and more common, so new tools and resources are needed to group such high dimensional data using clustering analysis. Different clustering algorithms can group data very differently. Therefore, there is a need to determine the best groupings in a given dataset using the most suitable clustering algorithm for that data. This paper presents the R package optCluster as an efficient way for users to evaluate up to ten clustering algorithms, ultimately determining the optimal algorithm and optimal number of clusters for a given set of data. The selected clustering algorithms are evaluated by as many as nine validation measures classified as “biological”, “internal”, or “stability”, and the final result is obtained through a weighted rank aggregation algorithm based on the calculated validation scores. Two examples using this package are presented, one with a microarray dataset and the other with an RNA-Seq dataset. These two examples highlight the capabilities the optCluster package and demonstrate its usefulness as a tool in cluster analysis

Predictions of Backbone Dynamics in Intrinsically Disordered Proteins Using De Novo Fragment-Based Protein Structure Predictions

Intrinsically disordaered proteins (IDPs) are a prevalent phenomenon with over 30% of human proteins estimated to have long disordered regions. Computational methods are widely used to study IDPs, however, nearly all treat disorder in a binary fashion, not accounting for the structural heterogeneity present in disordered regions. Here, we present a new de novo method, FRAGFOLD-IDP, which addresses this problem. Using 200 protein structural ensembles derived from NMR, we show that FRAGFOLD-IDP achieves superior results compared to methods which can predict related data (NMR order parameter, or crystallographic B-factor). FRAGFOLD-IDP produces very good predictions for 33.5% of cases and helps to get a better insight into the dynamics of the disordered ensembles. The results also show it is not necessary to predict the correct fold of the protein to reliably predict per-residue fluctuations. It implies that disorder is a local property and it does not depend on the fold. Our results are orthogonal to DynaMine, the only other method significantly better than the naïve prediction. We therefore combine these two using a neural network. FRAGFOLD-IDP enables better insight into backbone dynamics in IDPs and opens exciting possibilities for the design of disordered ensembles, disorder-to-order transitions, or design for protein dynamics

The chemistry and evolution of enzyme function: isomerases as a case study

The study of the evolution of proteins has been traditionally undertaken from a sequence and structural point of view. However any attempt to understand how protein function changes during evolution benefits from consistent definitions of function and robust approaches to quantitatively compare them. The function of enzymes is described as their ability to catalyse biochemical reactions according to the Enzyme Commission (EC). This dissertation explores aspects of the chemistry and evolution of a small class of enzymes catalysing geometrical and structural rearrangements between isomers, the isomerases (EC 5). A comprehensive analysis of the overall chemistry of isomerase reactions based on bond changes, reaction centres and substrates and products revealed that isomerase reactions are chemically diverse and difficult to classify using a hierarchical system. Although racemases and epimerases (EC 5.1) and cis-trans isomerases (EC 5.2) are sensibly grouped according to changes of stereochemistry, the overall chemistry of intramolecular oxidoreductases (EC 5.3), intramolecular transferases (EC 5.4) and intramolecular lyases (EC 5.5) is challenging. The subclass \other isomerases" (EC 5.99) sits apart from other subclasses and exhibits great diversity. The current classification of isomerases in six subclasses reduces to two subclasses if the type of isomerism is considered. In addition, the separation of groups of isomerases sharing similar chemistry such as oxidosqualene cyclases and pseudouridine synthases from chemically complex sub-subclasses like intramolecular transferases acting on \other groups" (EC 5.4.99) might also improve the classification. An overview of the evolution of isomerase function in superfamilies revealed three main findings. First, isomerases are more likely to evolve new functions in different EC primary classes, especially lyases (EC 4), rather than evolve to perform different isomerase reactions. Second, isomerases change their overall chemistry and conserve the structure of their substrates and products more often than conserving the chemistry and changing substrates and products. Last, the relationship between sequence and functional similarity suggests that correlations should be investigated on the basis of closely related enzymes. Although previous research assumes a one-to-one relationship between EC number and biochemical reaction, almost one-third of all known EC numbers are linked to more than one biochemical reaction. This complexity was characterised for isomerase reactions and used to develop an approach to automatically explore it across the entire EC classification. Remarkably, about 30% of the EC numbers bearing more than one reaction are linked to different types of reactions, bearing key differences in catalysed bond changes. Several recommendations to improve the description of complex biochemical reaction data in the EC classification were proposed. This dissertation explores enzymes from a functional perspective as an alternative to classical studies based on homology. This standpoint might prove useful to help to search for sequence candidates for orphan enzymes and in the design of enzymes with novel activities

PFClust : a novel parameter free clustering algorithm

Background: We present the algorithm PFClust (Parameter Free Clustering), which is able automatically to cluster data and identify a suitable number of clusters to group them into without requiring any parameters to be specified by the user. The algorithm partitions a dataset into a number of clusters that share some common attributes, such as their minimum expectation value and variance of intra-cluster similarity. A set of n objects can be clustered into any number of clusters from one to n, and there are many different hierarchical and partitional, agglomerative and divisive, clustering methodologies available that can be used to do this. Nonetheless, automatically determining the number of clusters present in a dataset constitutes a significant challenge for clustering algorithms. Identifying a putative optimum number of clusters to group the objects into involves computing and evaluating a range of clusterings with different numbers of clusters. However, there is no agreed or unique definition of optimum in this context. Thus, we test PFClust on datasets for which an external gold standard of 'correct' cluster definitions exists, noting that this division into clusters may be suboptimal according to other reasonable criteria. PFClust is heuristic in the sense that it cannot be described in terms of optimising any single simply-expressed metric over the space of possible clusterings. Results: We validate PFClust firstly with reference to a number of synthetic datasets consisting of 2D vectors, showing that its clustering performance is at least equal to that of six other leading methodologies -- even though five of the other methods are told in advance how many clusters to use. We also demonstrate the ability of PFClust to classify the three dimensional structures of protein domains, using a set of folds taken from the structural bioinformatics database CATH. Conclusions: We show that PFClust is able to cluster the test datasets a little better, on average, than any of the other algorithms, and furthermore is able to do this without the need to specify any external parameters. Results on the synthetic datasets demonstrate that PFClust generates meaningful clusters, while our algorithm also shows excellent agreement with the correct assignments for a dataset extracted from the CATH part-manually curated classification of protein domain structures.Publisher PDFPeer reviewe

PFClust: an optimised implementation of a parameter-free clustering algorithm

This work was supported by the World Anti-Doping Agency and the Scottish Universities Life Sciences Alliance.Background: A well-known problem in cluster analysis is finding an optimal number of clusters reflecting the inherent structure of the data. PFClust is a partitioning-based clustering algorithm capable, unlike many widely-used clustering algorithms, of automatically proposing an optimal number of clusters for the data. Results: The results of tests on various types of data showed that PFClust can discover clusters of arbitrary shapes, sizes and densities. The previous implementation of the algorithm had already been successfully used to cluster large macromolecular structures and small druglike compounds. We have greatly improved the algorithm by a more efficient implementation, which enables PFClust to process large data sets acceptably fast. Conclusions: In this paper we present a new optimized implementation of the PFClust algorithm that runs considerably faster than the original.Publisher PDFPeer reviewe