Stress-Induced Mechanotransduction: Some Preliminaries

2003 ◽  
Author(s):  
Mohammad R. Kaazempur-Mofrad ◽  
Peter J. Mack ◽  
Helene Karcher ◽  
Javad Golji ◽  
Roger G. Kamm
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Structural Changes ◽  
Protein Complexes ◽  
Element Model ◽  
Cytoskeletal Proteins ◽  
Signaling Cascades ◽  
Mechanical Stimuli ◽  
Underlying Mechanisms ◽  
Biochemical Signals

Mechanical stimuli affect nearly every aspect of cellular function, yet the underlying mechanisms of transduction of force into biochemical signals are not clearly understood. One hypothesis is that forces transmitted via individual proteins, either at the site of cell adhesion to its surroundings or within the stress-bearing members of the cytoskeleton, cause conformational changes that change their binding affinity to other intracellular molecules. This altered equilibrium state can subsequently initiate biochemical signaling cascades of produce immediate structural changes. This paper addresses the distribution of forces within the cell resulting from specific mechanical stimuli, computed using a 3-D multi compartment, continuum, viscoelastic finite element model, and uses these to estimate the forces transmitted by individual proteins and protein complexes. These levels of force are compared to those known to produce conformational changes in cytoskeletal proteins, as speculated from magnetocytometry observations and computed by molecular dynamics.

scholarly journals DNA tension-modulated translocation and loop extrusion by SMC complexes revealed by molecular dynamics simulations

2021 ◽  
Author(s):  
Stefanos S Nomidis ◽  
Enrico Carlon ◽  
Stephan Gruber ◽  
John F Marko
Keyword(s):  
Molecular Dynamics ◽  
Structural Changes ◽  
Protein Complexes ◽  
Power Stroke ◽  
End Points ◽  
Domains Of Life ◽  
Dynamics Simulations ◽  
Fixed End ◽  
Atp Binding And Hydrolysis ◽  
Low Tension

Structural Maintenance of Chromosomes (SMC) protein complexes play essential roles in genome folding and organization across all domains of life. In order to determine how the activities of these large (about 50 nm) complexes are controlled by ATP binding and hydrolysis, we have developed a molecular dynamics (MD) model that realistically accounts for thermal conformational motions of SMC and DNA. The model SMCs make use of DNA flexibility and looping, together with an ATP-induced "power stroke", to capture and transport DNA segments, so as to robustly translocate along DNA. This process is sensitive to DNA tension: at low tension (about 0.1 pN), the model performs steps of roughly 60 nm size, while, at higher tension, a distinct inchworm-like translocation mode appears, with steps that depend on SMC arm flexibility. By permanently tethering DNA to an experimentally-observed additional binding site ("safety belt"), the same model performs loop extrusion. We find that the dependence of loop extrusion on DNA tension is remarkably different when DNA tension is fixed vs when DNA end points are fixed: Loop extrusion reversal occurs above 0.5 pN for fixed tension, while loop extrusion stalling without reversal occurs at about 2 pN for fixed end points. Our model quantitatively matches recent experimental results on condensin and cohesin, and makes a number of clear predictions. Finally we investigate how specific structural changes affect the SMC function, which is testable in experiments on varied or mutant SMCs.

scholarly journals Conformational changes in myeloperoxidase induced by ubiquitin and NETs containing free ISG15 from systemic lupus erythematosus patients promote a pro-inflammatory cytokine response in CD4+ T cells

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Daniel Alberto Carrillo-Vázquez ◽  
Eduardo Jardón-Valadez ◽  
Jiram Torres-Ruiz ◽  
Guillermo Juárez-Vega ◽  
José Luis Maravillas-Montero ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Molecular Dynamics ◽  
Conformational Changes ◽  
Lupus Erythematosus ◽  
Structural Changes ◽  
Hydration Status ◽  
Healthy Controls ◽  
Heme Group ◽  
Systemic Lupus ◽  
The Impact

Abstract Background Neutrophil extracellular traps (NETs) from patients with systemic lupus erythematosus (SLE) are characterized by lower ubiquitylation and myeloperoxidase (MPO) as a substrate. The structural and functional effect of such modification and if there are additional post-translational modifications (PTMs) are unknown. Methods To assess the expression and functional role of PTMs in NETs of patients with SLE; reactivation, proliferation and cytokine production was evaluated by flow cytometry using co-cultures with dendritic cells (DC) and CD4+ from SLE patients and healthy controls. The impact of ubiquitylation on MPO was assessed by molecular dynamics. The expression of ISG15 in NETs was evaluated by immunofluorescence and Western Blot. Results Fifteen patients with SLE and ten healthy controls were included. In the co-cultures of CD4+ lymphocytes with DC stimulated with ubiquitylated MPO or recombinant MPO, a higher expression of IFNγ and IL-17A was found in CD4+ from SLE patients (p < 0.05). Furthermore, with DC stimulated with ubiquitylated MPO a trend towards increased expression of CD25 and Ki67 was found in lupus CD4+ lymphocytes, while the opposite was documented in controls (p < 0.05). Through molecular dynamics we found the K129-K488-K505 residues of MPO as susceptible to ubiquitylation. Ubiquitylation affects the hydration status of the HEME group depending on the residue to which it is conjugated. R239 was found near by the HEME group when the ubiquitin was in K488-K505. In addition, we found greater expression of ISG15 in the SLE NETs vs controls (p < 0.05), colocalization with H2B (r = 0.81) only in SLE samples and increased production of IFNγ in PBMCs stimulated with lupus NETs compared to healthy controls NETs. Conclusion The ubiquitylated MPO has a differential effect on the induction of reactivation of CD4+ lymphocytes in patients with SLE, which may be related to structural changes by ubiquitylation at the catalytic site of MPO. Besides a lower ubiquitylation pattern, NETs of patients with SLE are characterized by the expression of ISG15, and the induction of IFNγ by Th1 cells.

scholarly journals Mechanotransduction in T Cell Development, Differentiation and Function

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 364 ◽  
Author(s):  
Muaz Rushdi ◽  
Kaitao Li ◽  
Zhou Yuan ◽  
Stefano Travaglino ◽  
Arash Grakoui ◽  
...  
Keyword(s):  
T Cells ◽  
Life Cycle ◽  
T Cell ◽  
Conformational Changes ◽  
The Body ◽  
Mechanical Stimuli ◽  
Holistic Understanding ◽  
Ligand Interactions ◽  
And Function ◽  
Biochemical Signals

Cells in the body are actively engaging with their environments that include both biochemical and biophysical aspects. The process by which cells convert mechanical stimuli from their environment to intracellular biochemical signals is known as mechanotransduction. Exemplifying the reliance on mechanotransduction for their development, differentiation and function are T cells, which are central to adaptive immune responses. T cell mechanoimmunology is an emerging field that studies how T cells sense, respond and adapt to the mechanical cues that they encounter throughout their life cycle. Here we review different stages of the T cell’s life cycle where existing studies have shown important effects of mechanical force or matrix stiffness on a T cell as sensed through its surface molecules, including modulating receptor–ligand interactions, inducing protein conformational changes, triggering signal transduction, amplifying antigen discrimination and ensuring directed targeted cell killing. We suggest that including mechanical considerations in the immunological studies of T cells would inform a more holistic understanding of their development, differentiation and function.

scholarly journals NAPS update: network analysis of molecular dynamics data and protein–nucleic acid complexes

2019 ◽  
Vol 47 (W1) ◽  
pp. W462-W470 ◽  
Author(s):  
Broto Chakrabarty ◽  
Varun Naganathan ◽  
Kanak Garg ◽  
Yash Agarwal ◽  
Nita Parekh
Keyword(s):  
Molecular Dynamics ◽  
Nucleic Acid ◽  
Network Analysis ◽  
Conformational Changes ◽  
Protein Complexes ◽  
Md Simulations ◽  
Network Construction ◽  
Dynamic Correlation ◽  
Residue Interaction ◽  
Protein Nucleic Acid

Abstract Network theory is now a method of choice to gain insights in understanding protein structure, folding and function. In combination with molecular dynamics (MD) simulations, it is an invaluable tool with widespread applications such as analyzing subtle conformational changes and flexibility regions in proteins, dynamic correlation analysis across distant regions for allosteric communications, in drug design to reveal alternative binding pockets for drugs, etc. Updated version of NAPS now facilitates network analysis of the complete repertoire of these biomolecules, i.e., proteins, protein–protein/nucleic acid complexes, MD trajectories, and RNA. Various options provided for analysis of MD trajectories include individual network construction and analysis of intermediate time-steps, comparative analysis of these networks, construction and analysis of average network of the ensemble of trajectories and dynamic cross-correlations. For protein–nucleic acid complexes, networks of the whole complex as well as that of the interface can be constructed and analyzed. For analysis of proteins, protein–protein complexes and MD trajectories, network construction based on inter-residue interaction energies with realistic edge-weights obtained from standard force fields is provided to capture the atomistic details. Updated version of NAPS also provides improved visualization features, interactive plots and bulk execution. URL: http://bioinf.iiit.ac.in/NAPS/

scholarly journals Molecular Dynamics of SARS-CoV-2 Nsp1 Structural Changes Associated with Variant Mutations

2021 ◽  
Author(s):  
Shokouh Rezaei ◽  
Yahya Sefidbakht ◽  
Filipe Pereira
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Structural Changes ◽  
Structure And Function ◽  
Dynamics Simulation ◽  
Structural Protein ◽  
Wild Type ◽  
Deletion Mutations ◽  
And Function

Abstract SARS-CoV-2 non-structural protein 1 (Nsp1) is a virulence factor that inhibits the translation of host mRNAs and interact with viral RNA. Despite the relevance of Nsp1, few studies have been conducted to understand the effect of mutations on Nsp1 structure and function. Here, we provide a molecular dynamics simulation of SARS-CoV-2 Nsp1, wild type and variants. We found that SARS-CoV-2 Nsp1 has a more Rg value than SARS-CoV-1 Nsp1, with indicate an effect on the folding protein. This result suggest that SARS-CoV-2 Nsp1 can more easily approach the active site of the ribosome compared to SARS-CoV-1 Nsp1. In addition, we found that the C-terminal of the SARS-CoV-2 Nsp1, in particular residues 164 to 170, are more flexible than other regions of SARS-CoV-2 Nsp1 and SARS-CoV-1 Nsp1, confirming the role of this region in the interaction with the 40S subunit. Moreover, multiple deletion mutations have been found in the N/C-terminal of the SARS-CoV-2 Nsp1, which seems the effect of SARS-CoV-2 Nsp1 multiple deletions is greater than that of substitutions. Among all deletions, D156-158 and D80-90 may destabilize the protein structure and possibly increase the virulence of the SARS-CoV-2. Overall, our findings reinforce the importance of studying Nsp1 conformational changes in new variants and its effect on virulence of SARS-CoV-2.

scholarly journals An enhanced-sampling MD-based protocol for molecular docking

2018 ◽  
Author(s):  
Andrea Basciu ◽  
Giuliano Malloci ◽  
Fabio Pietrucci ◽  
Alexandre M. J. J. Bonvin ◽  
Attilio V. Vargiu
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Drug Design ◽  
Binding Site ◽  
Conformational Changes ◽  
Protein Complexes ◽  
Structural Diversity ◽  
Collective Variables ◽  
Structure Based Drug Design ◽  
Ensemble Docking

AbstractUnderstanding molecular recognition of proteins by small molecules is key for drug design. Despite the number of experimental structures of ligand-protein complexes keeps growing, the number of available targets remains limited compared to the druggable genome, and structural diversity is generally low, which affects the chemical variance of putative lead compounds. From a computational perspective, molecular docking is widely used to mimic ligand-protein association in silico. Ensemble-docking approaches include flexibility through a set of different conformations of the protein obtained either experimentally or from computer simulations, e.g. molecular dynamics. However, structures prone to host (the correct) ligands are generally poorly sampled by standard molecular dynamics simulations of the apo protein. In order to address this limitation, we introduce a computational approach based on metadynamics simulations (EDES - Ensemble-Docking with Enhanced-sampling of pocket Shape) to generate druggable conformations of proteins only exploiting their apo structures. This is achieved by defining a set of collective variables that effectively sample different shapes of the binding site, ultimately mimicking the steric effect due to ligands to generate holo-like binding site geometries. We assessed the method on two challenging proteins undergoing different extents of conformational changes upon ligand binding. In both cases our protocol generated a significant fraction of structures featuring a low RMSD from the experimental holo conformation. Moreover, ensemble docking calculations using those conformations yielded native-like poses among the top ranked ones for both targets. This proof of concept study paves the route towards an automated workflow to generate druggable conformations of proteins, which should become a precious tool for structure-based drug design.

scholarly journals A Free-Energy Landscape Analysis of Calmodulin Obtained from an NMR Data-Utilized Multi-Scale Divide-and-Conquer Molecular Dynamics Simulation

Life ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1241
Author(s):  
Hiromitsu Shimoyama ◽  
Yasuteru Shigeta
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Structural Change ◽  
Conformational Changes ◽  
Calcium Binding ◽  
Structural Changes ◽  
Energy Landscape ◽  
Divide And Conquer ◽  
Free Energy Landscape ◽  
Multi Scale

Calmodulin (CaM) is a multifunctional calcium-binding protein, which regulates a variety of biochemical processes. CaM acts through its conformational changes and complex formation with its target enzymes. CaM consists of two globular domains (N-lobe and C-lobe) linked by an extended linker region. Upon calcium binding, the N-lobe and C-lobe undergo local conformational changes, followed by a major conformational change of the entire CaM to wrap the target enzyme. However, the regulation mechanisms, such as allosteric interactions, which regulate the large structural changes, are still unclear. In order to investigate the series of structural changes, the free-energy landscape of CaM was obtained by multi-scale divide-and-conquer molecular dynamics (MSDC-MD). The resultant free-energy landscape (FEL) shows that the Ca2+ bound CaM (holo-CaM) would take an experimentally famous elongated structure, which can be formed in the early stage of structural change, by breaking the inter-domain interactions. The FEL also shows that important interactions complete the structural change from the elongated structure to the ring-like structure. In addition, the FEL might give a guiding principle to predict mutational sites in CaM. In this study, it was demonstrated that the movement process of macroscopic variables on the FEL may be diffusive to some extent, and then, the MSDC-MD is suitable to the parallel computation.

scholarly journals BODIPY Dyes as Probes and Sensors to Study Amyloid-β-Related Processes

Biosensors ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 192
Author(s):  
Sergei V. Dzyuba
Keyword(s):  
Small Molecule ◽  
Conformational Changes ◽  
Self Assembly ◽  
Structural Changes ◽  
Photophysical Properties ◽  
Amyloid Β ◽  
Amyloid Formation ◽  
Diverse Range ◽  
Aβ Peptides ◽  
Underlying Mechanisms

Amyloid formation plays a major role in a number of neurodegenerative diseases, including Alzheimer’s disease. Amyloid-β peptides (Aβ) are one of the primary markers associated with this pathology. Aβ aggregates exhibit a diverse range of morphologies with distinct pathological activities. Recognition of the Aβ aggregates by using small molecule-based probes and sensors should not only enhance understanding of the underlying mechanisms of amyloid formation, but also facilitate the development of therapeutic strategies to interfere with amyloid neurotoxicity. BODIPY (boron dipyrrin) dyes are among the most versatile small molecule fluorophores. BODIPY scaffolds could be functionalized to tune their photophysical properties to the desired ranges as well as to adapt these dyes to various types of conditions and environments. Thus, BODIPY dyes could be viewed as unique platforms for the design of probes and sensors that are capable of detecting and tracking structural changes of various Aβ aggregates. This review summarizes currently available examples of BODIPY dyes that have been used to investigate conformational changes of Aβ peptides, self-assembly processes of Aβ, as well as Aβ interactions with various molecules.

scholarly journals Structural Changes of Sarco/Endoplasmic Reticulum Ca2+-ATPase Induced by Rutin Arachidonate: A Molecular Dynamics Study

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 214
Author(s):  
Yoel Rodríguez ◽  
Magdaléna Májeková
Keyword(s):  
Molecular Dynamics ◽  
Endoplasmic Reticulum ◽  
Conformational Changes ◽  
Calcium Ions ◽  
Structural Changes ◽  
Acid Group ◽  
Bilayer Membrane ◽  
Salt Bridges ◽  
Drug Candidates ◽  
Dynamics Simulations

Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) maintains the level of calcium concentration in cells by pumping calcium ions from the cytoplasm to the lumen while undergoing substantial conformational changes, which can be stabilized or prevented by various compounds. Here we attempted to clarify the molecular mechanism of action of new inhibitor rutin arachidonate, one of the series of the acylated rutin derivatives. We performed molecular dynamics simulations of SERCA1a protein bound to rutin arachidonate positioned in a pure dipalmitoylphosphatidylcholine bilayer membrane. Our study predicted the molecular basis for the binding of rutin arachidonate towards SERCA1a in the vicinity of the binding site of calcium ions and near the location of the well-known inhibitor thapsigargin. The stable hydrogen bond between Glu771 and rutin arachidonate plays a key role in the binding. SERCA1a is kept in the E2 conformation preventing the formation of important salt bridges between the side chains of several residues, primarily Glu90 and Lys297. All in all, the structural changes induced by the binding of rutin arachidonate to SERCA1a may shift proton balance near the titrable residues Glu771 and Glu309 into neutral species, hence preventing the binding of calcium ions to the transmembrane binding sites and thus affecting calcium homeostasis. Our results could lead towards the design of new types of inhibitors, potential drug candidates for cancer treatment, which could be anchored to the transmembrane region of SERCA1a by a lipophilic fatty acid group.

scholarly journals Fluorescence resonance energy transfer and protein-induced fluorescence enhancement as synergetic multi-scale molecular rulers

2016 ◽  
Author(s):  
Evelyn Ploetz ◽  
Eitan Lerner ◽  
Florence Husada ◽  
Martin Roelfs ◽  
SangYoon Chung ◽  
...  
Keyword(s):  
Energy Transfer ◽  
Single Molecule ◽  
Conformational Changes ◽  
Transcription Initiation ◽  
Structural Changes ◽  
Fluorescence Enhancement ◽  
Protein Complexes ◽  
Fundamental Problem ◽  
Resonance Energy Transfer ◽  
Resonance Energy

ABSTRACTAdvanced microscopy methods allow obtaining information on (dynamic) conformational changes in biomolecules via measuring a single molecular distance in the structure. It is, however, extremely challenging to capture the full depth of a three-dimensional biochemical state, binding-related structural changes or conformational cross-talk in multi-protein complexes using one-dimensional assays. In this paper we address this fundamental problem by extending the standard molecular ruler based on Förster resonance energy transfer (FRET) into a two-dimensional assay via its combination with protein-induced fluorescence enhancement (PIFE). We show that donor brightness (viaPIFE) and energy transfer efficiency (viaFRET) can simultaneously report on e.g., the conformational state of dsDNA following its interaction with unlabelled proteins (BamHI, EcoRV, T7 DNA polymerase gp5/trx). The PIFE-FRET assay uses established labelling protocols and single molecule fluorescence detection schemes (alternating-laser excitation, ALEX). Besides quantitative studies of PIFE and FRET ruler characteristics, we outline possible applications of ALEX-based PIFE-FRET for single-molecule studies with diffusing and immobilized molecules. Finally, we study transcription initiation and scrunching ofE. coliRNA-polymerase with PIFE-FRET and provide direct evidence for the physical presence and vicinity of the polymerase that causes structural changes and scrunching of the transcriptional DNA bubble.

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