49,784 research outputs found
FLORA: a novel method to predict protein function from structure in diverse superfamilies
Predicting protein function from structure remains an active area of interest, particularly for the structural genomics initiatives where a substantial number of structures are initially solved with little or no functional characterisation. Although global structure comparison methods can be used to transfer functional annotations, the relationship between fold and function is complex, particularly in functionally diverse superfamilies that have evolved through different secondary structure embellishments to a common structural core. The majority of prediction algorithms employ local templates built on known or predicted functional residues. Here, we present a novel method (FLORA) that automatically generates structural motifs associated with different functional sub-families (FSGs) within functionally diverse domain superfamilies. Templates are created purely on the basis of their specificity for a given FSG, and the method makes no prior prediction of functional sites, nor assumes specific physico-chemical properties of residues. FLORA is able to accurately discriminate between homologous domains with different functions and substantially outperforms (a 2–3 fold increase in coverage at low error rates) popular structure comparison methods and a leading function prediction method. We benchmark FLORA on a large data set of enzyme superfamilies from all three major protein classes (α, β, αβ) and demonstrate the functional relevance of the motifs it identifies. We also provide novel predictions of enzymatic activity for a large number of structures solved by the Protein Structure Initiative. Overall, we show that FLORA is able to effectively detect functionally similar protein domain structures by purely using patterns of structural conservation of all residues
Data-driven network alignment
Biological network alignment (NA) aims to find a node mapping between
species' molecular networks that uncovers similar network regions, thus
allowing for transfer of functional knowledge between the aligned nodes.
However, current NA methods do not end up aligning functionally related nodes.
A likely reason is that they assume it is topologically similar nodes that are
functionally related. However, we show that this assumption does not hold well.
So, a paradigm shift is needed with how the NA problem is approached. We
redefine NA as a data-driven framework, TARA (daTA-dRiven network Alignment),
which attempts to learn the relationship between topological relatedness and
functional relatedness without assuming that topological relatedness
corresponds to topological similarity, like traditional NA methods do. TARA
trains a classifier to predict whether two nodes from different networks are
functionally related based on their network topological patterns. We find that
TARA is able to make accurate predictions. TARA then takes each pair of nodes
that are predicted as related to be part of an alignment. Like traditional NA
methods, TARA uses this alignment for the across-species transfer of functional
knowledge. Clearly, TARA as currently implemented uses topological but not
protein sequence information for this task. We find that TARA outperforms
existing state-of-the-art NA methods that also use topological information,
WAVE and SANA, and even outperforms or complements a state-of-the-art NA method
that uses both topological and sequence information, PrimAlign. Hence, adding
sequence information to TARA, which is our future work, is likely to further
improve its performance
miSTAR : miRNA target prediction through modeling quantitative and qualitative miRNA binding site information in a stacked model structure
In microRNA (miRNA) target prediction, typically two levels of information need to be modeled: the number of potential miRNA binding sites present in a target mRNA and the genomic context of each individual site. Single model structures insufficiently cope with this complex training data structure, consisting of feature vectors of unequal length as a consequence of the varying number of miRNA binding sites in different mRNAs. To circumvent this problem, we developed a two-layered, stacked model, in which the influence of binding site context is separately modeled. Using logistic regression and random forests, we applied the stacked model approach to a unique data set of 7990 probed miRNA-mRNA interactions, hereby including the largest number of miRNAs in model training to date. Compared to lower-complexity models, a particular stacked model, named miSTAR (miRNA stacked model target prediction; www.mi-star.org), displays a higher general performance and precision on top scoring predictions. More importantly, our model outperforms published and widely used miRNA target prediction algorithms. Finally, we highlight flaws in cross-validation schemes for evaluation of miRNA target prediction models and adopt a more fair and stringent approach
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
A structural view of microRNA-target recognition
It is well established that the correct identification of the messenger RNA targeted by a given microRNA (miRNA) is a difficult problem, and that available methods all suffer from low specificity. We hypothesize that the correct identification of the pairing should take into account the effect of the Argonaute protein (AGO), an essential catalyst of the recognition process. Therefore, we developed a strategy named MiREN for building and scoring three-dimensional models of the ternary complex formed by AGO, a miRNA and 22 nt of a target mRNA that putatively interacts with it. We show here that MiREN can be used to assess the likelihood that an RNA molecule is the target of a given miRNA and that this approach is more accurate than other existing methods, usually based on sequence or sequence-related features. Our results also suggest that AGO plays a relevant role in the selection of the miRNA targets. Our method can represent an additional step for refining predictions made by faster but less accurate classical methods for the identification of miRNA targets
CURRENTS AND THEIR COUPLINGS IN THE WEAK SECTOR OF THE STANDARD MODEL
Beta-decay and muon-capture experiments in nuclei are reviewed. The conserved
vector current hypothesis is confirmed through the observed constancy of the
vector coupling constant determined from the superallowed Fermi transitions and
from the measurement of the weak-magnetism term in mirror Gamow-Teller
transitions. The axial-vector and pseudoscalar coupling constants in the
nucleon are determined from neutron decay and muon capture on the proton
respectively. In finite nuclei, evidence for these coupling constants being
reduced relative to their free-nucleon values is discussed. Meson-exchange
currents are shown to be an important correction to the time-like part of the
axial current as evident in first-forbidden beta decays. Tests of the Standard
Model are discussed, as well as extensions beyond it involving right-hand
currents and scalar interactions.Comment: 67 pages, plain LaTex, uses worldsci.sty, two figures embedded in
manuscript as tex statements. A chapter for a book entitled 'The Nucleus as a
Laboratory for Studying Symmetries and Fundamental Interactions', eds. E.M.
Henley and W.C. Haxto
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