Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Mechanics and kinetics of dynamic instability.

ABSTRACT: During dynamic instability, self-assembling microtubules (MTs) stochastically alternate between phases of growth and shrinkage. This process is driven by the presence of two distinct states of MT subunits, GTP- and GDP-bound tubulin dimers, that have different structural properties. Here, we use a combination of analysis and computer simulations to study the mechanical and kinetic regulation of dynamic instability in three-dimensional (3D) self-assembling MTs. Our model quantifies how the 3D structure and kinetics of the distinct states of tubulin dimers determine the mechanical stability of MTs. We further show that dynamic instability is influenced by the presence of quenched disorder in the state of the tubulin subunit as reflected in the fraction of non-hydrolysed tubulin. Our results connect the 3D geometry, kinetics and statistical mechanics of these tubular assemblies within a single framework, and may be applicable to other self-assembled systems where these same processes are at play.

SUBMITTER: Michaels TC

PROVIDER: S-EPMC7213977 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Mechanics and kinetics of dynamic instability.

Michaels Thomas Ct TC Feng Shuo S Liang Haiyi H Mahadevan L L

eLife 20200511

During dynamic instability, self-assembling microtubules (MTs) stochastically alternate between phases of growth and shrinkage. This process is driven by the presence of two distinct states of MT subunits, GTP- and GDP-bound tubulin dimers, that have different structural properties. Here, we use a combination of analysis and computer simulations to study the mechanical and kinetic regulation of dynamic instability in three-dimensional (3D) self-assembling MTs. Our model quantifies how the 3D str ...[more]

PMID: 32392128

Similar Datasets

Actin kinetics shapes cortical network structure and mechanics.

Project description:The actin cortex of animal cells is the main determinant of cellular mechanics. The continuous turnover of cortical actin filaments enables cells to quickly respond to stimuli. Recent work has shown that most of the cortical actin is generated by only two actin nucleators, the Arp2/3 complex and the formin Diaph1. However, our understanding of their interplay, their kinetics, and the length distribution of the filaments that they nucleate within living cells is poor. Such knowledge is necessary for a thorough comprehension of cellular processes and cell mechanics from basic polymer physics principles. We determined cortical assembly rates in living cells by using single-molecule fluorescence imaging in combination with stochastic simulations. We find that formin-nucleated filaments are, on average, 10 times longer than Arp2/3-nucleated filaments. Although formin-generated filaments represent less than 10% of all actin filaments, mechanical measurements indicate that they are important determinants of cortical elasticity. Tuning the activity of actin nucleators to alter filament length distribution may thus be a mechanism allowing cells to adjust their macroscopic mechanical properties to their physiological needs.

| S-EPMC4846455 | biostudies-literature

Active Mechanics Reveal Molecular-Scale Force Kinetics in Living Oocytes.

Project description:Active diffusion of intracellular components is emerging as an important process in cell biology. This process is mediated by complex assemblies of molecular motors and cytoskeletal filaments that drive force generation in the cytoplasm and facilitate enhanced motion. The kinetics of molecular motors have been precisely characterized in vitro by single molecule approaches, but their in vivo behavior remains elusive. Here, we study the active diffusion of vesicles in mouse oocytes, where this process plays a key role in nuclear positioning during development, and combine an experimental and theoretical framework to extract molecular-scale force kinetics (force, power stroke, and velocity) of the in vivo active process. Assuming a single dominant process, we find that the nonequilibrium activity induces rapid kicks of duration τ ∼ 300 μs resulting in an average force of F ∼ 0.4 pN on vesicles in in vivo oocytes, remarkably similar to the kinetics of in vitro myosin-V. Our results reveal that measuring in vivo active fluctuations allows extraction of the molecular-scale activity in agreement with single-molecule studies and demonstrates a mesoscopic framework to access force kinetics.

| S-EPMC5954280 | biostudies-literature

Structure, Mechanics, and Instability of Fibrin Clot Infected with Staphylococcus epidermidis.

Project description:Health care-associated infection, over half of which can be attributed to indwelling medical devices, is a strong risk factor for thromboembolism. Although most experimental models of medical device infection draw upon isolated bacterial biofilms, in fact there is no infection without host protein contribution. Here we study, to our knowledge, a new model for medical device infection-that of an infected fibrin clot-and show that the common blood-borne pathogen Staphylococcus epidermidis influences this in vitro model of a blood clot mechanically and structurally on both microscopic and macroscopic scales. Bacteria present during clot formation produce a visibly disorganized microstructure that increases clot stiffness and triggers mechanical instability over time. Our results provide insight into the observed correlation between medical device infection and thromboembolism; the increase in model clot heterogeneity shows that S. epidermidis can rupture a fibrin clot. The resultant embolization of the infected clot can contribute to the systemic dissemination of the pathogen.

| S-EPMC5685636 | biostudies-literature

Multiscale mechanobiology: Coupling models of adhesion kinetics and nonlinear tissue mechanics.

Project description:The mechanical behavior of tissues at the macroscale is tightly coupled to cellular activity at the microscale. Dermal wound healing is a prominent example of a complex system in which multiscale mechanics regulate restoration of tissue form and function. In cutaneous wound healing, a fibrin matrix is populated by fibroblasts migrating in from a surrounding tissue made mostly out of collagen. Fibroblasts both respond to mechanical cues, such as fiber alignment and stiffness, as well as exert active stresses needed for wound closure. Here, we develop a multiscale model with a two-way coupling between a microscale cell adhesion model and a macroscale tissue mechanics model. Starting from the well-known model of adhesion kinetics proposed by Bell, we extend the formulation to account for nonlinear mechanics of fibrin and collagen and show how this nonlinear response naturally captures stretch-driven mechanosensing. We then embed the new nonlinear adhesion model into a custom finite element implementation of tissue mechanical equilibrium. Strains and stresses at the tissue level are coupled with the solution of the microscale adhesion model at each integration point of the finite element mesh. In addition, solution of the adhesion model is coupled with the active contractile stress of the cell population. The multiscale model successfully captures the mechanical response of biopolymer fibers and gels, contractile stresses generated by fibroblasts, and stress-strain contours observed during wound healing. We anticipate that this framework will not only increase our understanding of how mechanical cues guide cellular behavior in cutaneous wound healing, but will also be helpful in the study of mechanobiology, growth, and remodeling in other tissues.

| S-EPMC8874030 | biostudies-literature

Tekscan analysis programs (TAP) for quantifying dynamic contact mechanics.

Project description:This short communication provides details on customized Tekscan Analysis Programs (TAP) which extract comprehensive contact mechanics metrics from piezoelectric sensors in articulating joints across repeated loading cycles. The code provides functionality to identify regions of interest (ROI), compute contact mechanic metrics, and compare contact mechanics across multiple test conditions or knees. Further, the variability of identifying ROIs was quantified between seven different users and compared to an expert. Overall, the contribution of four variables were studied: two knee specimens; two points in the gait cycle; two averaging methods; and seven observers, to determine if variations in these values played a role in accurately quantifying the ROI. The relative error between the force ratio from each observer's ROI and the expert ROI was calculated as the output of interest. A multivariate linear mixed effects model was fit to the four variables for the relative error with an observer- and knee-specific random intercept. Results from the fitted model showed a statistically significant difference at the 0.05 level in the mean relative errors at the two gait points. Additionally, variability in the relative errors attributed to the observer, knee, and random errors was quantified. To reduce variability amongst users, by ensuring low inter-observer variability and increasing segmentation accuracy of knee contact mechanics, a training module and manual have been included as supplemental material. By sharing this code and training manual, we envisage that it can be used and modified to analyze outputs from a range of sensors, joints, and test conditions.

| S-EPMC10150386 | biostudies-literature

Hydrogels with Reversible Mechanics to Probe Dynamic Cell Microenvironments.

Project description:The relationship between ECM mechanics and cell behavior is dynamic, as cells remodel and respond to changes in their local environment. Most in vitro substrates are static and supraphysiologically stiff; thus, platforms with dynamic and reversible mechanical changes are needed. Herein, we developed hyaluronic acid-based substrates capable of sequential photodegradation and photoinitiated crosslinking reactions to soften and then stiffen the hydrogels over a physiologically relevant range of moduli. Reversible mechanical signaling to adhered cells was demonstrated with human mesenchymal stem cells. In situ hydrogel softening (from ca. 14 to 3.5 kPa) led to a decrease in the cell area and nuclear localization of YAP/TAZ, and subsequent stiffening (from ca. 3.5 to 28 kPa) increased the cell area and nuclear localization of YAP/TAZ. Each photoreaction was cytocompatible and tunable, rendering this platform amenable to studies of dynamic mechanics on cell behavior across many cell types and contexts.

| S-EPMC5668133 | biostudies-literature

Mechanics of dynamic compression plate application in fracture fixation.

Project description:BackgroundDynamic compression plating is a fundamental type of bone fracture fixation used to generate interfragmentary compression. The goal of this study was to investigate the mechanics of the surgical application of these plates, specifically how plate prebend, screw location, fracture gap, and applied torque influence the resulting compressive pressures.MethodsSynthetic bones with transverse fractures were fixed with locking compression plates. One side of the fracture was fixed with locking screws. On the other side of the fracture, a nonlocking screw was inserted eccentrically to induce interfragmentary compression. A pressure mapping sensor within the fracture gap was used to record the resulting pressure distribution. Plate prebends of 0 mm, 1.5 mm, and 3 mm were tested. Three locations of the eccentric screw, four levels of screw torque, and two initial fracture gap conditions also were tested.FindingsWith increasing plate prebend, fracture compression pressures shifted significantly toward the far cortex; however, compression force decreased (P < 0.05). The 1.5 mm prebend plate resulted in the greatest contact area. Increasing screw torque generally resulted in greater fracture compression force. The introduction of a 1 mm fracture gap at the far cortex prior to dynamic compression resulted in little or no fracture compression.InterpretationThe model showed that increasing plate prebend results in an increasing shift of fracture compression pressures toward the far cortex; however, this is accompanied by decreases in compressive force. Initial fracture gaps at the far cortex can result in little or no compression.

| S-EPMC11091841 | biostudies-literature

Dynamic graphical models of molecular kinetics.

Project description:Most current molecular dynamics simulation and analysis methods rely on the idea that the molecular system can be represented by a single global state (e.g., a Markov state in a Markov state model [MSM]). In this approach, molecules can be extensively sampled and analyzed when they only possess a few metastable states, such as small- to medium-sized proteins. However, this approach breaks down in frustrated systems and in large protein assemblies, where the number of global metastable states may grow exponentially with the system size. To address this problem, we here introduce dynamic graphical models (DGMs) that describe molecules as assemblies of coupled subsystems, akin to how spins interact in the Ising model. The change of each subsystem state is only governed by the states of itself and its neighbors. DGMs require fewer parameters than MSMs or other global state models; in particular, we do not need to observe all global system configurations to characterize them. Therefore, DGMs can predict previously unobserved molecular configurations. As a proof of concept, we demonstrate that DGMs can faithfully describe molecular thermodynamics and kinetics and predict previously unobserved metastable states for Ising models and protein simulations.

| S-EPMC6660760 | biostudies-literature

Torsin ATPases: Harnessing Dynamic Instability for Function.

Project description:Torsins are essential, disease-relevant AAA+ (ATPases associated with various cellular activities) proteins residing in the endoplasmic reticulum and perinuclear space, where they are implicated in a variety of cellular functions. Recently, new structural and functional details about Torsins have emerged that will have a profound influence on unraveling the precise mechanistic details of their yet-unknown mode of action in the cell. While Torsins are phylogenetically related to Clp/HSP100 proteins, they exhibit comparatively weak ATPase activities, which are tightly controlled by virtue of an active site complementation through accessory cofactors. This control mechanism is offset by a TorsinA mutation implicated in the severe movement disorder DYT1 dystonia, suggesting a critical role for the functional Torsin-cofactor interplay in vivo. Notably, TorsinA lacks aromatic pore loops that are both conserved and critical for the processive unfolding activity of Clp/HSP100 proteins. Based on these distinctive yet defining features, we discuss how the apparent dynamic nature of the Torsin-cofactor system can inform emerging models and hypotheses for Torsin complex formation and function. Specifically, we propose that the dynamic assembly and disassembly of the Torsin/cofactor system is a critical property that is required for Torsins' functional roles in nuclear trafficking and nuclear pore complex assembly or homeostasis that merit further exploration. Insights obtained from these future studies will be a valuable addition to our understanding of disease etiology of DYT1 dystonia.

| S-EPMC5425593 | biostudies-literature

Regulatory light chain mutations associated with cardiomyopathy affect myosin mechanics and kinetics.

Project description:The myosin regulatory light chain (RLC) wraps around the alpha-helical neck region of myosin. This neck region has been proposed to act as a lever arm, amplifying small conformational changes in the myosin head to generate motion. The RLC serves an important structural role, supporting the myosin neck region and a modulatory role, tuning the kinetics of the actin myosin interaction. Given the importance of the RLC, it is not surprising that mutations of the RLC can lead to familial hypertrophic cardiomyopathy (FHC), the leading cause of sudden cardiac death in people under 30. Population studies identified two FHC mutations located near the cationic binding site of the RLC, R58Q and N47K. Although these mutations are close in sequence, they differ in clinical presentation and prognosis, with R58Q showing a more severe phenotype. We examined the molecular based changes in myosin that are responsible for the disease phenotype by purifying myosin from transgenic mouse hearts expressing mutant myosins and examining actin filament sliding using the in vitro motility assay. We found that both R58Q and N47K show reductions in force compared to the wild type that could result in compensatory hypertrophy. Furthermore, we observed a higher ATPase rate and an increased activation at submaximal calcium levels for the R58Q myosin that could lead to decreased efficiency and incomplete cardiac relaxation, potentially explaining the more severe phenotype for the R58Q mutation.

| S-EPMC2675789 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data