43,384 research outputs found
The interplay of descriptor-based computational analysis with pharmacophore modeling builds the basis for a novel classification scheme for feruloyl esterases
One of the most intriguing groups of enzymes, the feruloyl esterases (FAEs), is ubiquitous in both simple and complex organisms. FAEs have gained importance in biofuel, medicine and food industries due to their capability of acting on a large range of substrates for cleaving ester bonds and synthesizing high-added value molecules through esterification and transesterification reactions. During the past two decades extensive studies have been carried out on the production and partial characterization of FAEs from fungi, while much less is known about FAEs of bacterial or plant origin. Initial classification studies on FAEs were restricted on sequence similarity and substrate specificity on just four model substrates and considered only a handful of FAEs belonging to the fungal kingdom. This study centers on the descriptor-based classification and structural analysis of experimentally verified and putative FAEs; nevertheless, the framework presented here is applicable to every poorly characterized enzyme family. 365 FAE-related sequences of fungal, bacterial and plantae origin were collected and they were clustered using Self Organizing Maps followed by k-means clustering into distinct groups based on amino acid composition and physico-chemical composition descriptors derived from the respective amino acid sequence. A Support Vector Machine model was subsequently constructed for the classification of new FAEs into the pre-assigned clusters. The model successfully recognized 98.2% of the training sequences and all the sequences of the blind test. The underlying functionality of the 12 proposed FAE families was validated against a combination of prediction tools and published experimental data. Another important aspect of the present work involves the development of pharmacophore models for the new FAE families, for which sufficient information on known substrates existed. Knowing the pharmacophoric features of a small molecule that are essential for binding to the members of a certain family opens a window of opportunities for tailored applications of FAEs
Identification of functionally related enzymes by learning-to-rank methods
Enzyme sequences and structures are routinely used in the biological sciences
as queries to search for functionally related enzymes in online databases. To
this end, one usually departs from some notion of similarity, comparing two
enzymes by looking for correspondences in their sequences, structures or
surfaces. For a given query, the search operation results in a ranking of the
enzymes in the database, from very similar to dissimilar enzymes, while
information about the biological function of annotated database enzymes is
ignored.
In this work we show that rankings of that kind can be substantially improved
by applying kernel-based learning algorithms. This approach enables the
detection of statistical dependencies between similarities of the active cleft
and the biological function of annotated enzymes. This is in contrast to
search-based approaches, which do not take annotated training data into
account. Similarity measures based on the active cleft are known to outperform
sequence-based or structure-based measures under certain conditions. We
consider the Enzyme Commission (EC) classification hierarchy for obtaining
annotated enzymes during the training phase. The results of a set of sizeable
experiments indicate a consistent and significant improvement for a set of
similarity measures that exploit information about small cavities in the
surface of enzymes
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Evolutionary and molecular foundations of multiple contemporary functions of the nitroreductase superfamily.
Insight regarding how diverse enzymatic functions and reactions have evolved from ancestral scaffolds is fundamental to understanding chemical and evolutionary biology, and for the exploitation of enzymes for biotechnology. We undertook an extensive computational analysis using a unique and comprehensive combination of tools that include large-scale phylogenetic reconstruction to determine the sequence, structural, and functional relationships of the functionally diverse flavin mononucleotide-dependent nitroreductase (NTR) superfamily (>24,000 sequences from all domains of life, 54 structures, and >10 enzymatic functions). Our results suggest an evolutionary model in which contemporary subgroups of the superfamily have diverged in a radial manner from a minimal flavin-binding scaffold. We identified the structural design principle for this divergence: Insertions at key positions in the minimal scaffold that, combined with the fixation of key residues, have led to functional specialization. These results will aid future efforts to delineate the emergence of functional diversity in enzyme superfamilies, provide clues for functional inference for superfamily members of unknown function, and facilitate rational redesign of the NTR scaffold
Kernel matrix regression
We address the problem of filling missing entries in a kernel Gram matrix,
given a related full Gram matrix. We attack this problem from the viewpoint of
regression, assuming that the two kernel matrices can be considered as
explanatory variables and response variables, respectively. We propose a
variant of the regression model based on the underlying features in the
reproducing kernel Hilbert space by modifying the idea of kernel canonical
correlation analysis, and we estimate the missing entries by fitting this model
to the existing samples. We obtain promising experimental results on gene
network inference and protein 3D structure prediction from genomic datasets. We
also discuss the relationship with the em-algorithm based on information
geometry
Extracting Biomolecular Interactions Using Semantic Parsing of Biomedical Text
We advance the state of the art in biomolecular interaction extraction with
three contributions: (i) We show that deep, Abstract Meaning Representations
(AMR) significantly improve the accuracy of a biomolecular interaction
extraction system when compared to a baseline that relies solely on surface-
and syntax-based features; (ii) In contrast with previous approaches that infer
relations on a sentence-by-sentence basis, we expand our framework to enable
consistent predictions over sets of sentences (documents); (iii) We further
modify and expand a graph kernel learning framework to enable concurrent
exploitation of automatically induced AMR (semantic) and dependency structure
(syntactic) representations. Our experiments show that our approach yields
interaction extraction systems that are more robust in environments where there
is a significant mismatch between training and test conditions.Comment: Appearing in Proceedings of the Thirtieth AAAI Conference on
Artificial Intelligence (AAAI-16
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