Dissecting Molecular Principles of the Hsp90 Chaperone Regulation by Allosteric Modulators Using a Hierarchical Simulation Approach and Network Modeling of Allosteric Interactions: Conformational Selection Dictates the Diversity of Protein Responses and Ligand-Specific Functional Mechanisms

2020 ◽  
Vol 16 (10) ◽  
pp. 6656-6677
Author(s):  
Lindy Astl ◽  
Gabrielle Stetz ◽  
Gennady M. Verkhivker
Keyword(s):  
Network Modeling ◽  
Allosteric Modulators ◽  
Simulation Approach ◽  
Conformational Selection ◽  
Allosteric Interactions ◽  
Hsp90 Chaperone ◽  
Functional Mechanisms

scholarly journals Coevolutionary Analysis and Perturbation-Based Network Modeling of the SARS-CoV-2 Spike Protein Complexes with Antibodies: Binding-Induced Control of Dynamics, Allosteric Interactions and Signaling

2021 ◽  
Author(s):  
Gennady M. Verkhivker ◽  
Luisa Di Paola
Keyword(s):  
Structural Changes ◽  
Molecular Mechanisms ◽  
Specific Binding ◽  
Network Modeling ◽  
Signal Propagation ◽  
Spike Protein ◽  
Hierarchical Network ◽  
Functional Regions ◽  
Allosteric Interactions ◽  
Spike Proteins

AbstractThe structural and biochemical studies of the SARS-CoV-2 spike glycoproteins and complexes with highly potent antibodies have revealed multiple conformation-dependent epitopes highlighting the link between conformational plasticity of spike proteins and capacity for eliciting specific binding and broad neutralization responses. In this study, we used coevolutionary analysis, molecular simulations, and perturbation-based hierarchical network modeling of the SARS-CoV-2 S complexes with H014, S309, S2M11 and S2E12 antibodies targeting distinct epitopes to explore molecular mechanisms underlying binding-induced modulation of dynamics, stability and allosteric signaling in the spike protein trimers. The results of this study revealed key regulatory centers that can govern allosteric interactions and communications in the SARS-CoV-2 spike proteins. Through coevolutionary analysis of the SARS-CoV-2 spike proteins, we identified highly coevolving hotspots and functional clusters forming coevolutionary networks. The results revealed significant coevolutionary couplings between functional regions separated by the medium-range distances which may help to facilitate a functional cross-talk between distant allosteric regions in the SARS-CoV-2 spike complexes with antibodies. We also discovered a potential mechanism by which antibody-specific targeting of coevolutionary centers can allow for efficient modulation of allosteric interactions and signal propagation between remote functional regions. Using a hierarchical network modeling and perturbation-response scanning analysis, we demonstrated that binding of antibodies could leverage direct contacts with coevolutionary hotspots to allosterically restore and enhance couplings between spatially separated functional regions, thereby protecting the spike apparatus from membrane fusion. The results of this study also suggested that antibody binding can induce a switch from a moderately cooperative population-shift mechanism, governing structural changes of the ligand-free SARS-CoV-2 spike protein, to antibody-induced highly cooperative mechanism that can better withstand mutations in the functional regions without significant deleterious consequences for protein function. This study provides a novel insight into allosteric regulatory mechanisms of SARS-CoV-2 S proteins, showing that antibodies can modulate allosteric interactions and signaling of spike proteins, providing a plausible strategy for therapeutic intervention by targeting specific hotspots of allosteric interactions in the SARS-CoV-2 proteins.

scholarly journals The nicotinic acetylcholine receptor: a typical ‘allosteric machine’

2018 ◽  
Vol 373 (1749) ◽  
pp. 20170174 ◽  
Author(s):  
Jean-Pierre Changeux
Keyword(s):  
Ion Channel ◽  
Feedback Mechanism ◽  
Membrane Receptors ◽  
Steric Interaction ◽  
Allosteric Modulators ◽  
Pharmacological Agents ◽  
Allosteric Interactions ◽  
Regulatory Enzymes ◽  
Inhibitory Feedback ◽  
Dynamics Simulations

The concept of allosteric interaction was initially proposed to account for the inhibitory feedback mechanism mediated by bacterial regulatory enzymes. In contrast with the classical mechanism of competitive, steric, interaction between ligands for a common site, allosteric interactions take place between topographically distinct sites and are mediated by a discrete and reversible conformational change of the protein. The concept was soon extended to membrane receptors for neurotransmitters and shown to apply to the signal transduction process which, in the case of the acetylcholine nicotinic receptor (nAChR), links the ACh binding site to the ion channel. Pharmacological effectors, referred to as allosteric modulators, such as Ca 2+ ions and ivermectin, were discovered that enhance the transduction process when they bind to sites distinct from the orthosteric ACh site and the ion channel. The recent X-ray and electron microscopy structures, at atomic resolution, of the resting and active conformations of several homologues of the nAChR, in combination with atomistic molecular dynamics simulations reveal a stepwise quaternary transition in the transduction process with tertiary changes modifying the boundaries between subunits. These interfaces host orthosteric and allosteric modulatory sites which structural organization changes in the course of the transition. The nAChR appears as a typical allosteric machine. The model emerging from these studies has led to the conception and development of several new pharmacological agents. This article is part of a discussion meeting issue ‘Allostery and molecular machines’.

scholarly journals Elastic Network Modeling of Cellular Networks Unveils Sensor and Effector Genes that Control Information Flow

2021 ◽  
Author(s):  
Omer Acar ◽  
She Zhang ◽  
Ivet Bahar ◽  
Anne-Ruxandra Carvunis
Keyword(s):  
Cellular Networks ◽  
Long Range ◽  
Network Modeling ◽  
Genetic Network ◽  
Elastic Network Model ◽  
Elastic Network ◽  
Cellular Processes ◽  
Allosteric Interactions ◽  
Long Range Interactions ◽  
High Level

The high-level organization of the cell is embedded in long-range interactions that connect distinct cellular processes. Existing approaches for detecting long-range interactions consist of propagating information from source nodes through cellular networks, but the selection of source nodes is inherently biased by prior knowledge. Here, we sought to derive an unbiased view of long-range interactions by adapting a perturbation-response scanning strategy initially developed for identifying allosteric interactions within proteins. We deployed this strategy onto an elastic network model of the yeast genetic network. The genetic network revealed a superior propensity for long-range interactions relative to simulated networks with similar topology. Long-range interactions were detected systematically throughout the network and found to be enriched in specific biological processes. Furthermore, perturbation-response scanning identified the major sources and receivers of information in the network, named effector and sensor genes, respectively. Effectors formed dense clusters centrally integrated into the network, whereas sensors formed loosely connected antenna-shaped clusters. Long-range interactions between effector and sensor clusters represent the major paths of information in the network. Our results demonstrate that elastic network modeling of cellular networks constitutes a promising strategy to probe the high-level organization of the cell.

Tubulin structure at intermediate resolution

1995 ◽  
Vol 53 ◽  
pp. 852-853
Author(s):  
K. H. Downing ◽  
S. G. Wolf ◽  
E. Nogales
Keyword(s):  
High Resolution ◽  
Structural Data ◽  
Therapeutic Drug ◽  
Zinc Ions ◽  
Two Dimensional ◽  
X Ray Diffraction ◽  
X Ray ◽  
Negative Stain ◽  
Functional Mechanisms ◽  
Tubulin Structure

Microtubules are involved in a host of critical cell activities, many of which involve transport of organelles through the cell. Different sets of microtubules appear to form during the cell cycle for different functions. Knowledge of the structure of tubulin will be necessary in order to understand the various functional mechanisms of microtubule assemble, disassembly, and interaction with other molecules, but tubulin has so far resisted crystallization for x-ray diffraction studies. Fortuitously, in the presence of zinc ions, tubulin also forms two-dimensional, crystalline sheets that are ideally suited for study by electron microscopy. We have refined procedures for forming the sheets and preparing them for EM, and have been able to obtain high-resolution structural data that sheds light on the formation and stabilization of microtubules, and even the interaction with a therapeutic drug.Tubulin sheets had been extensively studied in negative stain, demonstrating that the same protofilament structure was formed in the sheets and microtubules. For high resolution studies, we have found that the sheets embedded in either glucose or tannin diffract to around 3 Å.

An empirical test of situational strength's functional mechanisms

2010 ◽  
Author(s):  
Irwin J. Jose ◽  
Rustin D. Meyer ◽  
Richard Hermida ◽  
Vivek Khare ◽  
Reeshad S. Dalal
Keyword(s):  
Empirical Test ◽  
Functional Mechanisms

Developments in 3D Echocardiography

2009 ◽  
Vol 5 (2) ◽  
pp. 10 ◽  
Author(s):  
Jose Luis Zamorano ◽  
Keyword(s):  
3D Echocardiography ◽  
Resonance Imaging ◽  
Clinical Tool ◽  
3D Images ◽  
Processing Power ◽  
2D Echocardiography ◽  
Automated Quantification ◽  
Heart Cycle ◽  
Functional Mechanisms ◽  
Full Volume

3D echocardiography (3DE) will gain increasing acceptance as a routine clinical tool as the technology evolves due to advances in technology and computer processing power. Images obtained from 3DE provide more accurate assessment of complex cardiac anatomy and sophisticated functional mechanisms compared with conventional 2D echocardiography (2DE), and are comparable to those achieved with magnetic resonance imaging. Many of the limitations associated with the early iterations of 3DE prevented their widespread clinical application. However, recent significant improvements in transducer and post-processing software technologies have addressed many of these issues. Furthermore, the most recent advances in the ability to image the entire heart in realtime and fully automated quantification have poised 3DE to become more ubiquitous in clinical routine. Realtime 3DE (RT3DE) systems offer further improvements in the diagnostic and treatment planning capabilities of cardiac ultrasound. Innovations such as the ability to acquire non-stitched, realtime, full-volume 3D images of the heart in a single heart cycle promise to overcome some of the current limitations of current RT3DE systems, which acquire images over four to seven cardiac cycles, with the need for gating and the potential for stitch artefacts.

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