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Characterisation of FAD-family folds using a machine learning approach
Flavin adenine dinucleotide (FAD) and its derivatives play a crucial role in
biological processes. They are major organic cofactors and electron carriers
in both enzymatic activities and biochemical pathways. We have analysed
the relationships between sequence and structure of FAD-containing proteins
using a machine learning approach. Decision trees were generated using the
C4.5 algorithm as a means of automatically generating rules from biological
databases (TOPS, CATH and PDB). These rules were then used as
background knowledge for an ILP system to characterise the four different
classes of FAD-family folds classified in Dym and Eisenberg (2001). These
FAD-family folds are: glutathione reductase (GR), ferredoxin reductase (FR),
p-cresol methylhydroxylase (PCMH) and pyruvate oxidase (PO). Each FADfamily
was characterised by a set of rules. The “knowledge patterns”
generated from this approach are a set of rules containing conserved sequence
motifs, secondary structure sequence elements and folding information.
Every rule was then verified using statistical evaluation on the measured
significance of each rule. We show that this machine learning approach is
capable of learning and discovering interesting patterns from large biological
databases and can generate “knowledge patterns” that characterise the FADcontaining
proteins, and at the same time classify these proteins into four
different families
MEMOFinder: combining _de_ _novo_ motif prediction methods with a database of known motifs
*Background:* Methods for finding overrepresented sequence motifs are useful in several key areas of computational biology. They aim at detecting very weak signals responsible for biological processes requiring robust sequence identification like transcription-factor binding to DNA or docking sites in proteins. Currently, general performance of the model-based motif-finding methods is unsatisfactory; however, different methods are successful in different cases. This leads to the practical problem of combining results of different motif-finding tools, taking into account current knowledge collected in motif databases.
*Results:* We propose a new complete service allowing researchers to submit their sequences for analysis by four different motif-finding methods for clustering and comparison with a reference motif database. It is tailored for regulatory motif detection, however it allows for substantial amount of configuration regarding sequence background, motif database and parameters for motif-finding methods.
*Availability:* The method is available online as a webserver at: http://bioputer.mimuw.edu.pl/software/mmf/. In addition, the source code is released on a GNU General Public License
Motif Discovery through Predictive Modeling of Gene Regulation
We present MEDUSA, an integrative method for learning motif models of
transcription factor binding sites by incorporating promoter sequence and gene
expression data. We use a modern large-margin machine learning approach, based
on boosting, to enable feature selection from the high-dimensional search space
of candidate binding sequences while avoiding overfitting. At each iteration of
the algorithm, MEDUSA builds a motif model whose presence in the promoter
region of a gene, coupled with activity of a regulator in an experiment, is
predictive of differential expression. In this way, we learn motifs that are
functional and predictive of regulatory response rather than motifs that are
simply overrepresented in promoter sequences. Moreover, MEDUSA produces a model
of the transcriptional control logic that can predict the expression of any
gene in the organism, given the sequence of the promoter region of the target
gene and the expression state of a set of known or putative transcription
factors and signaling molecules. Each motif model is either a -length
sequence, a dimer, or a PSSM that is built by agglomerative probabilistic
clustering of sequences with similar boosting loss. By applying MEDUSA to a set
of environmental stress response expression data in yeast, we learn motifs
whose ability to predict differential expression of target genes outperforms
motifs from the TRANSFAC dataset and from a previously published candidate set
of PSSMs. We also show that MEDUSA retrieves many experimentally confirmed
binding sites associated with environmental stress response from the
literature.Comment: RECOMB 200
Automated linear motif discovery from protein interaction network
Master'sMASTER OF SCIENC
The benefits of in silico modeling to identify possible small-molecule drugs and their off-target interactions
Accepted for publication in a future issue of Future Medicinal Chemistry.The research into the use of small molecules as drugs continues to be a key driver in the development of molecular databases, computer-aided drug design software and collaborative platforms. The evolution of computational approaches is driven by the essential criteria that a drug molecule has to fulfill, from the affinity to targets to minimal side effects while having adequate absorption, distribution, metabolism, and excretion (ADME) properties. A combination of ligand- and structure-based drug development approaches is already used to obtain consensus predictions of small molecule activities and their off-target interactions. Further integration of these methods into easy-to-use workflows informed by systems biology could realize the full potential of available data in the drug discovery and reduce the attrition of drug candidates.Peer reviewe
Typing tumors using pathways selected by somatic evolution.
Many recent efforts to analyze cancer genomes involve aggregation of mutations within reference maps of molecular pathways and protein networks. Here, we find these pathway studies are impeded by molecular interactions that are functionally irrelevant to cancer or the patient's tumor type, as these interactions diminish the contrast of driver pathways relative to individual frequently mutated genes. This problem can be addressed by creating stringent tumor-specific networks of biophysical protein interactions, identified by signatures of epistatic selection during tumor evolution. Using such an evolutionarily selected pathway (ESP) map, we analyze the major cancer genome atlases to derive a hierarchical classification of tumor subtypes linked to characteristic mutated pathways. These pathways are clinically prognostic and predictive, including the TP53-AXIN-ARHGEF17 combination in liver and CYLC2-STK11-STK11IP in lung cancer, which we validate in independent cohorts. This ESP framework substantially improves the definition of cancer pathways and subtypes from tumor genome data
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