69,206 research outputs found
MRFalign: Protein Homology Detection through Alignment of Markov Random Fields
Sequence-based protein homology detection has been extensively studied and so
far the most sensitive method is based upon comparison of protein sequence
profiles, which are derived from multiple sequence alignment (MSA) of sequence
homologs in a protein family. A sequence profile is usually represented as a
position-specific scoring matrix (PSSM) or an HMM (Hidden Markov Model) and
accordingly PSSM-PSSM or HMM-HMM comparison is used for homolog detection. This
paper presents a new homology detection method MRFalign, consisting of three
key components: 1) a Markov Random Fields (MRF) representation of a protein
family; 2) a scoring function measuring similarity of two MRFs; and 3) an
efficient ADMM (Alternating Direction Method of Multipliers) algorithm aligning
two MRFs. Compared to HMM that can only model very short-range residue
correlation, MRFs can model long-range residue interaction pattern and thus,
encode information for the global 3D structure of a protein family.
Consequently, MRF-MRF comparison for remote homology detection shall be much
more sensitive than HMM-HMM or PSSM-PSSM comparison. Experiments confirm that
MRFalign outperforms several popular HMM or PSSM-based methods in terms of both
alignment accuracy and remote homology detection and that MRFalign works
particularly well for mainly beta proteins. For example, tested on the
benchmark SCOP40 (8353 proteins) for homology detection, PSSM-PSSM and HMM-HMM
succeed on 48% and 52% of proteins, respectively, at superfamily level, and on
15% and 27% of proteins, respectively, at fold level. In contrast, MRFalign
succeeds on 57.3% and 42.5% of proteins at superfamily and fold level,
respectively. This study implies that long-range residue interaction patterns
are very helpful for sequence-based homology detection. The software is
available for download at http://raptorx.uchicago.edu/download/.Comment: Accepted by both RECOMB 2014 and PLOS Computational Biolog
Composite structural motifs of binding sites for delineating biological functions of proteins
Most biological processes are described as a series of interactions between
proteins and other molecules, and interactions are in turn described in terms
of atomic structures. To annotate protein functions as sets of interaction
states at atomic resolution, and thereby to better understand the relation
between protein interactions and biological functions, we conducted exhaustive
all-against-all atomic structure comparisons of all known binding sites for
ligands including small molecules, proteins and nucleic acids, and identified
recurring elementary motifs. By integrating the elementary motifs associated
with each subunit, we defined composite motifs which represent
context-dependent combinations of elementary motifs. It is demonstrated that
function similarity can be better inferred from composite motif similarity
compared to the similarity of protein sequences or of individual binding sites.
By integrating the composite motifs associated with each protein function, we
define meta-composite motifs each of which is regarded as a time-independent
diagrammatic representation of a biological process. It is shown that
meta-composite motifs provide richer annotations of biological processes than
sequence clusters. The present results serve as a basis for bridging atomic
structures to higher-order biological phenomena by classification and
integration of binding site structures.Comment: 34 pages, 7 figure
DeepSF: deep convolutional neural network for mapping protein sequences to folds
Motivation
Protein fold recognition is an important problem in structural
bioinformatics. Almost all traditional fold recognition methods use sequence
(homology) comparison to indirectly predict the fold of a tar get protein based
on the fold of a template protein with known structure, which cannot explain
the relationship between sequence and fold. Only a few methods had been
developed to classify protein sequences into a small number of folds due to
methodological limitations, which are not generally useful in practice.
Results
We develop a deep 1D-convolution neural network (DeepSF) to directly classify
any protein se quence into one of 1195 known folds, which is useful for both
fold recognition and the study of se quence-structure relationship. Different
from traditional sequence alignment (comparison) based methods, our method
automatically extracts fold-related features from a protein sequence of any
length and map it to the fold space. We train and test our method on the
datasets curated from SCOP1.75, yielding a classification accuracy of 80.4%. On
the independent testing dataset curated from SCOP2.06, the classification
accuracy is 77.0%. We compare our method with a top profile profile alignment
method - HHSearch on hard template-based and template-free modeling targets of
CASP9-12 in terms of fold recognition accuracy. The accuracy of our method is
14.5%-29.1% higher than HHSearch on template-free modeling targets and
4.5%-16.7% higher on hard template-based modeling targets for top 1, 5, and 10
predicted folds. The hidden features extracted from sequence by our method is
robust against sequence mutation, insertion, deletion and truncation, and can
be used for other protein pattern recognition problems such as protein
clustering, comparison and ranking.Comment: 28 pages, 13 figure
Who Watches the Watchmen? An Appraisal of Benchmarks for Multiple Sequence Alignment
Multiple sequence alignment (MSA) is a fundamental and ubiquitous technique
in bioinformatics used to infer related residues among biological sequences.
Thus alignment accuracy is crucial to a vast range of analyses, often in ways
difficult to assess in those analyses. To compare the performance of different
aligners and help detect systematic errors in alignments, a number of
benchmarking strategies have been pursued. Here we present an overview of the
main strategies--based on simulation, consistency, protein structure, and
phylogeny--and discuss their different advantages and associated risks. We
outline a set of desirable characteristics for effective benchmarking, and
evaluate each strategy in light of them. We conclude that there is currently no
universally applicable means of benchmarking MSA, and that developers and users
of alignment tools should base their choice of benchmark depending on the
context of application--with a keen awareness of the assumptions underlying
each benchmarking strategy.Comment: Revie
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
metaSHARK: software for automated metabolic network prediction from DNA sequence and its application to the genomes of Plasmodium falciparum and Eimeria tenella
The metabolic SearcH And Reconstruction Kit
(metaSHARK) is a new fully automated software package
for the detection of enzyme-encoding genes
within unannotated genome data and their visualization
in the context of the surrounding metabolic network.
The gene detection package (SHARKhunt) runs
on a Linux systemand requires only a set of raw DNA
sequences (genomic, expressed sequence tag and/
or genome survey sequence) as input. Its output
may be uploaded to our web-based visualization
tool (SHARKview) for exploring and comparing data
from different organisms. We first demonstrate the
utility of the software by comparing its results for
the raw Plasmodium falciparum genome with the
manual annotations available at the PlasmoDB and
PlasmoCyc websites. We then apply SHARKhunt to
the unannotated genome sequences of the coccidian
parasite Eimeria tenella and observe that, at an
E-value cut-off of 10(-20), our software makes 142
additional assertions of enzymatic function compared
with a recent annotation package working
with translated open reading frame sequences. The
ability of the software to cope with low levels of
sequence coverage is investigated by analyzing
assemblies of the E.tenella genome at estimated
coverages from 0.5x to 7.5x. Lastly, as an example
of how metaSHARK can be used to evaluate the
genomic evidence for specific metabolic pathways,
we present a study of coenzyme A biosynthesis in
P.falciparum and E.tenella
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