scholarly journals Robust Determination of Protein Allosteric Signaling Pathways

2019 ◽  
Author(s):  
Wesley M. Botello-Smith ◽  
Yun Luo
Keyword(s):  
Signaling Pathways ◽  
Network Topology ◽  
Protein Function ◽  
Current Flow ◽  
Md Simulations ◽  
Electrical Network ◽  
Smoothing Function ◽  
Allosteric Enzyme ◽  
Improved Stability ◽  
Source And Sink

AbstractTo understand how protein function changes upon an allosteric perturbation, such as ligand binding and mutation, significant progress in characterizing allosteric network from molecular dynamics (MD) simulations has been made. However, determining which amino acid(s) play an essential role in the propagation of signals may prove challenging, even when the location of the source and sink is known for a protein or protein complex. This challenge is mainly due to the large fluctuations in protein dynamics that cause instability of the network topology within a single trajectory or between multiple replicas. To solve this problem, we introduce the current-flow betweenness scheme, originated from electrical network theory, to protein dynamical network analysis. To demonstrate the benefit of this new method, we chose a prototypic allosteric enzyme (IGPS or HisH-HisF dimer) as our benchmark system. Using multiple replicas of simulations and multiple network topology comparison metrics (edge ranking, path length, and node frequency), we show that the current-flow betweenness provides a significant improvement in the convergence of the allosteric networks. The improved stability of the network topology allows us to generate a delta-network between the apo and holo forms of the protein. We illustrated that the delta-network is a more rigorous way to capture the subtle changes in the networks that would otherwise be neglected by comparing node usage frequencies alone. We have also investigated the use of a linear smoothing function to improve the stability of the contact map. The methodology presented here is general and may be applied to other topology and weighting schemes. We thus conclude that, for determining protein signaling pathways between the pair(s) of source and sink, multiple MD simulation replicas are necessary and the current-flow betweenness scheme introduced here provides a more robust approach than the geodesic scheme based on correlation edge weighting.For Table of Contents Only

scholarly journals Robust Resistance Network Topology Design by Conic Optimization

2012 ◽  
Vol 16 ◽  
pp. 125 ◽  
Author(s):  
C. Roos ◽  
Y. Bai ◽  
D. Chaerani
Keyword(s):  
Linear Model ◽  
Network Topology ◽  
Design Problem ◽  
Topology Design ◽  
Electrical Network ◽  
Conic Optimization ◽  
External Current ◽  
Current Case ◽  
Resistor Network ◽  
Network Topology Design

After a brief introduction to the field of Conic Optimization we present an application to the (robust) resistor network topology design problem, where the goal is to design an electrical network containing resistors, such that the dissipation is minimal, given the external current values at the nodes of the network and assuming that the conductance values satisfy some normalizing constraint. We present a linear model for the single-current case and semidefinite models for multi-current cases. All models are illustrated by examples.  

scholarly journals Approaches to imaging unfolded secretory protein stress in living cells

2014 ◽  
Vol 1 (1) ◽  
Author(s):  
Patrick Lajoie ◽  
Elena N. Fazio ◽  
Erik L. Snapp
Keyword(s):  
Quality Control ◽  
Signaling Pathways ◽  
Protein Function ◽  
Secretory Pathway ◽  
Transcriptional Response ◽  
Secretory Protein ◽  
Model Systems ◽  
Er Quality Control ◽  
Unfolded Protein ◽  
Point Of Entry

AbstractThe endoplasmic reticulum (ER) is the point of entry of proteins into the secretory pathway. Nascent peptides interact with the ER quality control machinery that ensures correct folding of the nascent proteins. Failure to properly fold proteins can lead to loss of protein function and cytotoxic aggregation of misfolded proteins that can lead to cell death. To cope with increases in the ER unfolded secretory protein burden, cells have evolved the Unfolded Protein Response (UPR). The UPR is the primary signaling pathway that monitors the state of the ER folding environment. When the unfolded protein burden overwhelms the capacity of the ER quality control machinery, a state termed ER stress, sensor proteins detect accumulation of misfolded peptides and trigger the UPR transcriptional response. The UPR, which is conserved from yeast to mammals, consists of an ensemble of complex signaling pathways that aims at adapting the ER to the new misfolded protein load. To determine how different factors impact the ER folding environment, various tools and assays have been developed. In this review, we discuss recent advances in live cell imaging reporters and model systems that enable researchers to monitor changes in the unfolded secretory protein burden and activation of the UPR and its associated signaling pathways.

scholarly journals Protocols for fast simulations of protein structure flexibility using CABS-flex and SURPASS

2019 ◽  
Author(s):  
Aleksandra Badaczewska-Dawid ◽  
Andrzej Kolinski ◽  
Sebastian Kmiecik
Keyword(s):  
Protein Function ◽  
Md Simulation ◽  
Protein Structures ◽  
Md Simulations ◽  
System Size ◽  
Coarse Grained ◽  
Simulation Tools ◽  
Speed Up ◽  
Structure Flexibility ◽  
Computational Resources

SummaryConformational flexibility of protein structures can play an important role in protein function. The flexibility is often studied using computational methods, since experimental characterization can be difficult. Depending on protein system size; computational tools may require large computational resources or significant simplifications in the modeled systems to speed-up calculations. In this work, we present the protocols for efficient simulations of flexibility of folded protein structures that use coarse-grained simulation tools of different resolutions: medium, represented by CABS-flex, and low, represented by SUPRASS. We test the protocols using a set of 140 globular proteins and compare the results with structure fluctuations observed in MD simulations, ENM modeling and NMR ensembles. As demonstrated, CABS-flex predictions show high correlation to experimental and MD simulation data, while SURPASS is less accurate but promising in terms of future developments.

scholarly journals Electric network topology and method of transmission of electric energy

2019 ◽  
Vol 21 (4) ◽  
pp. 95-103
Author(s):  
N. I. Smolentsev ◽  
L. M. Chetoshnikova
Keyword(s):  
Energy Storage ◽  
Network Topology ◽  
Information Technologies ◽  
Electric Energy ◽  
Electrical Energy ◽  
Electrical Network ◽  
Energy Storage Devices ◽  
Electric Networks ◽  
Storage Devices ◽  
Asynchronous Method

The purpose of the work is to reduce losses and increase energy saving in electric networks. To achieve this goal, a multilevel topology of the electrical network and an asynchronous method for transferring electrical energy between nodes including a load, energy sources, energy storage devices connected in an appropriate manner are proposed. It is shown by the mathematical method that this network topology allows using energy storage devices controlled appropriately and using tele-information technologies to optimize the balance of electric energy in the network, achieving equality of the generated and consumed electricity. Such a network topology and a method of transmitting electrical energy can be the basis of digital technologies in the energy sector (ENERNET).

Identification of Critical Functional Modules and Signaling Pathways in Osteoporosis

2020 ◽  
Vol 15 ◽  
Author(s):  
Xiaowei Jiang ◽  
Pu Ying ◽  
Yingchao Shen ◽  
Yiming Miu ◽  
Wenbin Kong ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Differential Expression ◽  
Expression Analysis ◽  
Network Topology ◽  
Molecular Mechanisms ◽  
Differential Expression Analysis ◽  
Osteoclast Differentiation ◽  
Enrichment Analysis ◽  
Osteoclast Formation ◽  
Functional Modules

Background: Osteoporosis is the most common bone metabolic disease. Abnormal osteoclast formation and resorption play a fundamental role in osteoporosis pathogenesis. Recent researches have greatly broadened our understanding of molecular mechanisms of osteoporosis. However, the molecular mechanisms leading to osteoporosis are still not entirely clear. Objective: The purpose of this work is to study the critical regulatory genes, functional modules, and signaling pathways. Methods: Differential expression analysis, network topology-based analysis, and overrepresentation enrichment analysis (ORA) were used to identify differentially expressed genes (DEGs), gene subnetworks, and signaling pathways related to osteoporosis, respectively. Results: Differential expression analysis identified DEGs, such as POGLUT1, DAPK3 and NFKBIA, associated with osteoclastogenesis, which highlighted Notch, apoptosis and NF-kB signaling pathways. Network topology-based analysis identified the upregulated subnetwork characterized by EXOSC8 and DIS3L from the RNA exosome complex, and the downregulated subnetwork composed of histone deacetylases and the cofactors, MORF4L1 and JDP2. Furthermore, the overrepresentation enrichment analysis highlighted that corticotrophin-releasing hormone signaling pathway may affect osteoclastogenesis through its component NR4A1, and suppressing osteoclast differentiation and osteoclast bone resorption with urocortin (UCN). Conclusion: Our systematic analysis not only discovered novel molecular mechanisms, but also proposed potential drug targets for osteoporosis.

scholarly journals A novel carcinogenic PI3Kα mutation suggesting the role of helical domain in transmitting nSH2 regulatory signals to kinase domain

2020 ◽  
Author(s):  
Safoura Ghalamkari ◽  
Shahryar Alavi ◽  
Hamidreza Mianesaz ◽  
Farinaz Khosravian ◽  
Amir Bahreini ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Function ◽  
Md Simulations ◽  
Binding Pocket ◽  
Kinase Domain ◽  
The Novel ◽  
Mutant Proteins ◽  
Helical Domain ◽  
Three Samples

Abstract Background Mutations in PIK3CA, which encodes p110 subunit of PI3K class IA enzyme, are highly frequent in breast cancer. Here, we aimed to probe mutations in exon 9 of PIK3CA and computationally simulate their function. Method PCR/HRM and PCR/sequencing were used for mutation detection in 40 breast cancer specimens. The identified mutations were queried via in silico algorithms to check the pathogenicity. The molecular dynamics (MD) simulations were utilized to assess the function of mutant proteins. Result Three samples were found to harbor at least one of the E542K, E545K and L551Q mutations of which L511Q has not been reported previously. All mutations were confirmed to be pathogenic and MD simulations revealed their impact on protein function and regulation. The novel L551Q mutant dynamics was similar to that of previously found carcinogenic mutants, E542K and E545K. A functional role for the helical domain was also suggested by which the inhibitory signal of p85α is conducted to kinase domain via helical domain. Helical domain mutations lead to impairment of kinase domain allosteric regulation. Interestingly, our results show that p110α substrate binding pocket of helical domain in mutants may have differential affinity for enzyme substrates, including anit-p110α drugs. Conclusion The novel p110α L551Q mutation could has carcinogenic feature similar to previously known mutations.

scholarly journals Power electrical network topology detection using changes of phasor measurements in transient states

2019 ◽  
Vol 139 ◽  
pp. 01063
Author(s):  
Natalja Gotman ◽  
Galina Shumilova
Keyword(s):  
Neural Networks ◽  
Artificial Neural Networks ◽  
Network Topology ◽  
Short Circuit ◽  
Transient State ◽  
Test System ◽  
Experimental Results ◽  
Electrical Network ◽  
Phasor Measurements ◽  
Measurement Units

The solution of the problem of a topology detection of an electrical network on changing voltage and current phasors obtained from the phasor measurement units (PMUs) in a transient state using artificial neural networks (ANNs) is considered. Experimental results for the 14-bus test system to detect the failed line after short circuit and the line was turned on by an auto-reclosing device are presented.

scholarly journals Generalized logical model based on network topology to capture the dynamical trends of cellular signaling pathways

2016 ◽  
Vol 10 (S1) ◽  
Author(s):  
Fan Zhang ◽  
Haoting Chen ◽  
Li Na Zhao ◽  
Hui Liu ◽  
Teresa M. Przytycka ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Network Topology ◽  
Cellular Signaling ◽  
Logical Model ◽  
Model Based

scholarly journals Decoding the Molecular Effects of Atovaquone Linked Resistant Mutations on Plasmodium falciparum Cytb-ISP Complex in the Phospholipid Bilayer Membrane

2021 ◽  
Vol 22 (4) ◽  
pp. 2138
Author(s):  
Lorna Chebon-Bore ◽  
Taremekedzwa Allan Sanyanga ◽  
Colleen Varaidzo Manyumwa ◽  
Afrah Khairallah ◽  
Özlem Tastan Bishop
Keyword(s):  
Plasmodium Falciparum ◽  
Active Site ◽  
Protein Function ◽  
Hydrophobic Interactions ◽  
Point Mutations ◽  
Md Simulations ◽  
Resistance Mechanisms ◽  
Phospholipid Bilayer ◽  
Active Site Residues ◽  
Presence And Absence

Atovaquone (ATQ) is a drug used to prevent and treat malaria that functions by targeting the Plasmodium falciparum cytochrome b (PfCytb) protein. PfCytb catalyzes the transmembrane electron transfer (ET) pathway which maintains the mitochondrial membrane potential. The ubiquinol substrate binding site of the protein has heme bL, heme bH and iron-sulphur [2FE-2S] cluster cofactors that act as redox centers to aid in ET. Recent studies investigating ATQ resistance mechanisms have shown that point mutations of PfCytb confer resistance. Thus, understanding the resistance mechanisms at the molecular level via computational approaches incorporating phospholipid bilayer would help in the design of new efficacious drugs that are also capable of bypassing parasite resistance. With this knowledge gap, this article seeks to explore the effect of three drug resistant mutations Y268C, Y268N and Y268S on the PfCytb structure and function in the presence and absence of ATQ. To draw reliable conclusions, 350 ns all-atom membrane (POPC:POPE phospholipid bilayer) molecular dynamics (MD) simulations with derived metal parameters for the holo and ATQ-bound -proteins were performed. Thereafter, simulation outputs were analyzed using dynamic residue network (DRN) analysis. Across the triplicate MD runs, hydrophobic interactions, reported to be crucial in protein function were assessed. In both, the presence and absence of ATQ and a loss of key active site residue interactions were observed as a result of mutations. These active site residues included: Met 133, Trp136, Val140, Thr142, Ile258, Val259, Pro260 and Phe264. These changes to residue interactions are likely to destabilize the overall intra-protein residue communication network where the proteins’ function could be implicated. Protein dynamics of the ATQ-bound mutant complexes showed that they assumed a different pose to the wild-type, resulting in diminished residue interactions in the mutant proteins. In summary, this study presents insights on the possible effect of the mutations on ATQ drug activity causing resistance and describes accurate MD simulations in the presence of the lipid bilayer prior to conducting inhibitory drug discovery for the PfCytb-iron sulphur protein (Cytb-ISP) complex.

scholarly journals Investigating Protein-Protein Allosteric Network using Current-Flow Scheme

2018 ◽  
Author(s):  
Wesley M. Botello-Smith ◽  
Yun Luo
Keyword(s):  
Network Analysis ◽  
Current Flow ◽  
Signal Transmission ◽  
Dynamic Network ◽  
Contact Network ◽  
Smoothing Function ◽  
Inhibitory Protein ◽  
Atp Binding Site ◽  
Flow Scheme ◽  
Binding Interface

AbstractProtein dynamic network analysis provides a powerful tool for investigating protein allosteric regulation. We recently developed a current-flow betweenness scheme for protein network analysis and demonstrated that this method, i.e. using current-flow betweenness as edge weights, is more appropriate and more robust for investigating the signal transmission between two predefined protein residues or domains as compared with direct usage of correlation scores as edge weights. Here we seek to expand the current-flow scheme to study allosteric regulations involving protein-protein binding. Specifically, we investigated three gain-of-function mutations located at the binding interface of ALK2 (also known as ACVR1) kinase and its inhibitory protein FKBP12. We first searched for the optimal smoothing function for contact network construction and then calculated the subnetwork between FKBP12 protein and ALK2 ATP binding site using current-flow betweenness. By comparing the networks between the wild-type and three mutants, we have identified statistically significant changes in the protein-protein networks that are common among all three mutants that allosterically shift the kinase towards a catalytically competent configuration.

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