73,126 research outputs found
Allo-network drugs: Extension of the allosteric drug concept to protein-protein interaction and signaling networks
Allosteric drugs are usually more specific and have fewer side effects than orthosteric drugs targeting the same
protein. Here, we overview the current knowledge on allosteric signal transmission from the network point of view, and show that most intra-protein conformational changes may be dynamically transmitted across protein-protein interaction and signaling networks of the cell. Allo-network drugs influence the pharmacological target protein indirectly using specific inter-protein network pathways. We show that allo-network drugs may have a higher efficiency to change the networks of human cells than those of other organisms, and can be designed to have specific effects on cells in a diseased state. Finally, we summarize possible methods to identify allo-network drug targets and sites, which may develop to a promising new area of systems-based drug design
ModuLand plug-in for Cytoscape: determination of hierarchical layers of overlapping network modules and community centrality
Summary: The ModuLand plug-in provides Cytoscape users an algorithm for
determining extensively overlapping network modules. Moreover, it identifies
several hierarchical layers of modules, where meta-nodes of the higher
hierarchical layer represent modules of the lower layer. The tool assigns
module cores, which predict the function of the whole module, and determines
key nodes bridging two or multiple modules. The plug-in has a detailed
JAVA-based graphical interface with various colouring options. The ModuLand
tool can run on Windows, Linux, or Mac OS. We demonstrate its use on protein
structure and metabolic networks. Availability: The plug-in and its user guide
can be downloaded freely from: http://www.linkgroup.hu/modules.php. Contact:
[email protected] Supplementary information: Supplementary
information is available at Bioinformatics online.Comment: 39 pages, 1 figure and a Supplement with 9 figures and 10 table
CancerLinker: Explorations of Cancer Study Network
Interactive visualization tools are highly desirable to biologist and cancer
researchers to explore the complex structures, detect patterns and find out the
relationships among bio-molecules responsible for a cancer type. A pathway
contains various bio-molecules in different layers of the cell which is
responsible for specific cancer type. Researchers are highly interested in
understanding the relationships among the proteins of different pathways and
furthermore want to know how those proteins are interacting in different
pathways for various cancer types. Biologists find it useful to merge the data
of different cancer studies in a single network and see the relationships among
the different proteins which can help them detect the common proteins in cancer
studies and hence reveal the pattern of interactions of those proteins. We
introduce the CancerLinker, a visual analytic tool that helps researchers
explore cancer study interaction network. Twenty-six cancer studies are merged
to explore pathway data and bio-molecules relationships that can provide the
answers to some significant questions which are helpful in cancer research. The
CancerLinker also helps biologists explore the critical mutated proteins in
multiple cancer studies. A bubble graph is constructed to visualize common
protein based on its frequency and biological assemblies. Parallel coordinates
highlight patterns of patient profiles (obtained from cBioportal by WebAPI
services) on different attributes for a specified cancer studyComment: 7 pages, 9 figure
Computational identification of signalling pathways in Plasmodium falciparum
Malaria is one of the world’s most common and serious diseases causing death of about 3 million people
each year. Its most severe occurrence is caused by the protozoan Plasmodium falciparum. Reports have
shown that the resistance of the parasite to existing drugs is increasing. Therefore, there is a huge and
urgent need to discover and validate new drug or vaccine targets to enable the development of new
treatments for malaria. The ability to discover these drug or vaccine targets can only be enhanced from
our deep understanding of the detailed biology of the parasite, for example how cells function and how
proteins organize into modules such as metabolic, regulatory and signal transduction pathways. It has
been noted that the knowledge of signalling transduction pathways in Plasmodium is fundamental to aid
the design of new strategies against malaria. This work uses a linear-time algorithm for finding paths in a
network under modified biologically motivated constraints. We predicted several important signalling
transduction pathways in Plasmodium falciparum. We have predicted a viable signalling pathway
characterized in terms of the genes responsible that may be the PfPKB pathway recently elucidated in
Plasmodium falciparum. We obtained from the FIKK family, a signal transduction pathway that ends up on
a chloroquine resistance marker protein, which indicates that interference with FIKK proteins might
reverse Plasmodium falciparum from resistant to sensitive phenotype. We also proposed a hypothesis
that showed the FIKK proteins in this pathway as enabling the resistance parasite to have a mechanism
for releasing chloroquine (via an efflux process). Furthermore, we also predicted a signalling pathway
that may have been responsible for signalling the start of the invasion process of Red Blood Cell (RBC) by
the merozoites. It has been noted that the understanding of this pathway will give insight into the
parasite virulence and will facilitate rational vaccine design against merozoites invasion. And we have a
host of other predicted pathways, some of which have been used in this work to predict the functionality
of some proteins
Link communities reveal multiscale complexity in networks
Networks have become a key approach to understanding systems of interacting
objects, unifying the study of diverse phenomena including biological organisms
and human society. One crucial step when studying the structure and dynamics of
networks is to identify communities: groups of related nodes that correspond to
functional subunits such as protein complexes or social spheres. Communities in
networks often overlap such that nodes simultaneously belong to several groups.
Meanwhile, many networks are known to possess hierarchical organization, where
communities are recursively grouped into a hierarchical structure. However, the
fact that many real networks have communities with pervasive overlap, where
each and every node belongs to more than one group, has the consequence that a
global hierarchy of nodes cannot capture the relationships between overlapping
groups. Here we reinvent communities as groups of links rather than nodes and
show that this unorthodox approach successfully reconciles the antagonistic
organizing principles of overlapping communities and hierarchy. In contrast to
the existing literature, which has entirely focused on grouping nodes, link
communities naturally incorporate overlap while revealing hierarchical
organization. We find relevant link communities in many networks, including
major biological networks such as protein-protein interaction and metabolic
networks, and show that a large social network contains hierarchically
organized community structures spanning inner-city to regional scales while
maintaining pervasive overlap. Our results imply that link communities are
fundamental building blocks that reveal overlap and hierarchical organization
in networks to be two aspects of the same phenomenon.Comment: Main text and supplementary informatio
Structural Prediction of Protein–Protein Interactions by Docking: Application to Biomedical Problems
A huge amount of genetic information is available thanks to the recent advances in sequencing technologies and the larger computational capabilities, but the interpretation of such genetic data at phenotypic level remains elusive. One of the reasons is that proteins are not acting alone, but are specifically interacting with other proteins and biomolecules, forming intricate interaction networks that are essential for the majority of cell processes and pathological conditions. Thus, characterizing such interaction networks is an important step in understanding how information flows from gene to phenotype. Indeed, structural characterization of protein–protein interactions at atomic resolution has many applications in biomedicine, from diagnosis and vaccine design, to drug discovery. However, despite the advances of experimental structural determination, the number of interactions for which there is available structural data is still very small. In this context, a complementary approach is computational modeling of protein interactions by docking, which is usually composed of two major phases: (i) sampling of the possible binding modes between the interacting molecules and (ii) scoring for the identification of the correct orientations. In addition, prediction of interface and hot-spot residues is very useful in order to guide and interpret mutagenesis experiments, as well as to understand functional and mechanistic aspects of the interaction. Computational docking is already being applied to specific biomedical problems within the context of personalized medicine, for instance, helping to interpret pathological mutations involved in protein–protein interactions, or providing modeled structural data for drug discovery targeting protein–protein interactions.Spanish Ministry of Economy grant number BIO2016-79960-R; D.B.B. is supported by a
predoctoral fellowship from CONACyT; M.R. is supported by an FPI fellowship from the
Severo Ochoa program. We are grateful to the Joint BSC-CRG-IRB Programme in
Computational Biology.Peer ReviewedPostprint (author's final draft
The Energy Landscape, Folding Pathways and the Kinetics of a Knotted Protein
The folding pathway and rate coefficients of the folding of a knotted protein
are calculated for a potential energy function with minimal energetic
frustration. A kinetic transition network is constructed using the discrete
path sampling approach, and the resulting potential energy surface is
visualized by constructing disconnectivity graphs. Owing to topological
constraints, the low-lying portion of the landscape consists of three distinct
regions, corresponding to the native knotted state and to configurations where
either the N- or C-terminus is not yet folded into the knot. The fastest
folding pathways from denatured states exhibit early formation of the
N-terminus portion of the knot and a rate-determining step where the C-terminus
is incorporated. The low-lying minima with the N-terminus knotted and the
C-terminus free therefore constitute an off-pathway intermediate for this
model. The insertion of both the N- and C-termini into the knot occur late in
the folding process, creating large energy barriers that are the rate limiting
steps in the folding process. When compared to other protein folding proteins
of a similar length, this system folds over six orders of magnitude more
slowly.Comment: 19 page
Inter-protein sequence co-evolution predicts known physical interactions in bacterial ribosomes and the trp operon
Interaction between proteins is a fundamental mechanism that underlies
virtually all biological processes. Many important interactions are conserved
across a large variety of species. The need to maintain interaction leads to a
high degree of co-evolution between residues in the interface between partner
proteins. The inference of protein-protein interaction networks from the
rapidly growing sequence databases is one of the most formidable tasks in
systems biology today. We propose here a novel approach based on the
Direct-Coupling Analysis of the co-evolution between inter-protein residue
pairs. We use ribosomal and trp operon proteins as test cases: For the small
resp. large ribosomal subunit our approach predicts protein-interaction
partners at a true-positive rate of 70% resp. 90% within the first 10
predictions, with areas of 0.69 resp. 0.81 under the ROC curves for all
predictions. In the trp operon, it assigns the two largest interaction scores
to the only two interactions experimentally known. On the level of residue
interactions we show that for both the small and the large ribosomal subunit
our approach predicts interacting residues in the system with a true positive
rate of 60% and 85% in the first 20 predictions. We use artificial data to show
that the performance of our approach depends crucially on the size of the joint
multiple sequence alignments and analyze how many sequences would be necessary
for a perfect prediction if the sequences were sampled from the same model that
we use for prediction. Given the performance of our approach on the test data
we speculate that it can be used to detect new interactions, especially in the
light of the rapid growth of available sequence data
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