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At least 1,207 records · Page 67Linked to original sources

arXiv2013

Biophysics of filament length regulation by molecular motors

Regulating physical size is an essential problem that biological organisms must solve from the subcellular to the organismal scales, but it is not well understood what physical principles and mechanisms organisms use to sense and regulate their size. Any biophysical size-regulation scheme operates in a noisy environment and must be robust to other cellular dynamics and fluctuations. This work develops theory of filament length regulation inspired by recent experiments on kinesin-8 motor proteins, which move with directional bias on microtubule filaments and alter microtubule dynamics. Purified kinesin-8 motors can depolymerize chemically-stabilized microtubules. In the length-dependent depolymerization model, the rate of depolymerization tends to increase with filament length, because long filaments accumulate more motors at their tips and therefore shorten more quickly. When balanced with a constant filament growth rate, this mechanism can lead to a fixed polymer length. However, the mechanism by which kinesin-8 motors affect the length of dynamic microtubules in cells is less clear. We study the more biologically realistic problem of microtubule dynamic instability modulated by a motor-dependent increase in the filament catastrophe frequency. This leads to a significant decrease in the mean filament length and a narrowing of the filament length distribution. The results improve our understanding of the biophysics of length regulation in cells.

physics.bio-ph↗

arXiv2013

Control of ribosome traffic by position-dependent choice of synonymous codons

Messenger RNA encodes a sequence of amino acids by using codons. For most amino acids there are multiple synonymous codons that can encode the amino acid. The translation speed can vary from one codon to another, thus there is room for changing the ribosome speed while keeping the amino acid sequence and hence the resulting protein. Recently, it has been noticed that the choice of the synonymous codon, via the resulting distribution of slow- and fast-translated codons, affects not only on the average speed of one ribosome translating the messenger RNA (mRNA) but also might have an effect on nearby ribosomes by affecting the appearance of "traffic jams" where multiple ribosomes collide and form queues. To test this "context effect" further, we here investigate the effect of the sequence of synonymous codons on the ribosome traffic by using a ribosome traffic model with codon-dependent rates, estimated from experiments. We compare the ribosome traffic on wild type sequences and sequences where the synonymous codons were swapped randomly. By simulating translation of 87 genes, we demonstrate that the wild type sequences, especially those with a high bias in codon usage, tend to have the ability to reduce ribosome collisions, hence optimizing the cellular investment in the translation apparatus. The magnitude of such reduction of the translation time might have a significant impact on the cellular growth rate and thereby have importance for the survival of the species.

q-bio.SC↗

arXiv2013

Modelling the effect of myosin X motors on filopodia growth

We present a numerical simulation study of the dynamics of filopodial growth in the presence of active transport by myosin X motors. We employ both a microscopic agent-based model, which captures the stochasticity of the growth process, and a continuum mean-field theory which neglects fluctuations. We show that in the absence of motors, filopodia growth is overestimated by the continuum mean-field theory. Thus fluctuations slow down the growth, especially when the protrusions are driven by a small number (10 or less) of F-actin fibres, and when the force opposing growth (coming from membrane elasticity) is large enough. We also show that, with typical parameter values for eukaryotic cells, motors are unlikely to provide an actin transport mechanism which enhances filopodial size significantly, unless the G-actin concentration within the filopodium greatly exceeds that of the cytosol bulk. We explain these observations in terms of order-of-magnitude estimates of diffusion-induced and advection-induced growth of a bundle of Brownian ratchets.

physics.bio-ph↗

arXiv2014

Collective behavior of minus-ended motors in mitotic microtubule asters gliding towards DNA

Microtubules (MTs) nucleated by centrosomes form star-shaped structures referred to as asters. Aster motility and dynamics is vital for genome stability, cell division, polarization and differentiation. Asters move either towards the cell center or away from it. Here, we focus on the centering mechanism in a membrane independent system of Xenopus cytoplasmic egg extracts. Using live microscopy and single particle tracking, we find that asters move towards chromatinized DNA structures. The velocity and directionality profiles suggest a random walk with drift directed towards DNA. We have developed a theoretical model that can explain this movement as a result of a gradient of MT length dynamics and MT gliding on immobilized dynein motors. In simulations, the antagonistic action of the motor species on the radial array of MTs leads to a tug-of-war purely due to geometric considerations and aster motility resembles a directed random-walk. Additionally our model predicts that aster velocities do not change greatly with varying initial distance from DNA. The movement of asymmetric asters becomes increasingly super-diffusive with increasing motor density, but for symmetric asters it becomes less super-diffusive. The transition of symmetric asters from superdiffusive to diffusive mobility is the result of number fluctuations in bound motors in the tug-of-war. Overall, our model is in good agreement with experimental data in Xenopus cytoplasmic extracts and predicts novel features of the collective effects of motor-MT interactions.

q-bio.SC↗

arXiv2014

Distribution of lifetimes of kinetochore-microtubule attachments: interplay of energy landscape, molecular motors and microtubule (de-)polymerization

Before a cell divides into two daughter cells, chromosomes are replicated resulting in two sister chromosomes embracing each other. Each sister chromosome is bound to a separate proteinous structure, called kinetochore (kt), that captures the tip of a filamentous protein, called microtubule (MT). Two oppositely oriented MTs pull the two kts attached to two sister chromosomes thereby pulling the two sisters away from each other. Here we theoretically study an even simpler system, namely an isolated kt coupled to a single MT; this system mimics an {\it in-vitro} experiment where a single kt-MT attachment is reconstituted using purified extracts from budding yeast. Our models not only account for the experimentally observed "catch-bond-like" behavior of the kt-MT coupling, but also make new predictions on the probability distribution of the lifetimes of the attachments. In principle, our new predictions can be tested by analyzing the data collected in the {\it in-vitro} experiments provided the experiment is repeated sufficiently large number of times. Our theory provides a deep insight into the effects of (a) size, (b) energetics, and (c) stochastic kinetics of the kt-MT coupling on the distribution of the lifetimes of these attachments.

physics.bio-ph↗

arXiv2014

Effects of microtubule mechanics on hydrolysis and catastrophes

We introduce a model for microtubule mechanics containing lateral bonds between dimers in neighboring protofilaments, bending rigidity of dimers, and repulsive interactions between protofilaments modeling steric constraints to investigate the influence of mechanical forces on hydrolysis and catastrophes. We use the allosteric dimer model, where tubulin dimers are characterized by an equilibrium bending angle, which changes from $0^\circ$ to $22^\circ$ by hydrolysis of a dimer. This also affects the lateral interaction and bending energies and, thus, the mechanical equilibrium state of the microtubule. As hydrolysis gives rise to conformational changes in dimers, mechanical forces also influence the hydrolysis rates by mechanical energy changes modulating the hydrolysis rate. The interaction via the microtubule mechanics then gives rise to correlation effects in the hydrolysis dynamics, which have not been taken into account before. Assuming a dominant influence of mechanical energies on hydrolysis rates, we investigate the most probable hydrolysis pathways both for vectorial and random hydrolysis. Investigating the stability with respect to lateral bond rupture, we identify initiation configurations for catastrophes along the hydrolysis pathways and values for a lateral bond rupture force. If we allow for rupturing of lateral bonds between dimers in neighboring protofilaments above this threshold force, our model exhibits avalanche-like catastrophe events.

q-bio.SC↗

arXiv2014

Protein translocation without specific quality control in a computational model of the Tat system

The twin-arginine translocation (Tat) system transports folded proteins of various sizes across both bacterial and plant thylakoid membranes. The membrane-associated TatA protein is an essential component of the Tat translocon, and a broad distribution of different sized TatA-clusters is observed in bacterial membranes. We assume that the size dynamics of TatA clusters are affected by substrate binding, unbinding, and translocation to associated TatBC clusters, where clusters with bound translocation substrates favour growth and those without associated substrates favour shrinkage. With a stochastic model of substrate binding and cluster dynamics, we numerically determine the TatA cluster size distribution. We include a proportion of targeted but non-translocatable (NT) substrates, with the simplifying hypothesis that the substrate translocatability does not directly affect cluster dynamical rate constants or substrate binding or unbinding rates. This amounts to a translocation model without specific quality control. Nevertheless, NT substrates will remain associated with TatA clusters until unbound and so will affect cluster sizes and translocation rates. We find that the number of larger TatA clusters depends on the NT fraction $f$. The translocation rate can be optimized by tuning the rate of spontaneous substrate unbinding, $Γ_U$. We present an analytically solvable three-state model of substrate translocation without cluster size dynamics that follows our computed translocation rates, and that is consistent with {\em in vitro} Tat-translocation data in the presence of NT substrates.

q-bio.SC↗

arXiv2014

Motor proteins traffic regulation by supply-demand balance of resources

In cells and in vitro assays the number of motor proteins involved in biological transport processes is far from being unlimited. The cytoskeletal binding sites are in contact with the same finite reservoir of motors (either the cytosol or the flow chamber) and hence compete for recruiting the available motors, potentially depleting the reservoir and affecting cytoskeletal transport. In this work we provide a theoretical framework to study, analytically and numerically, how motor density profiles and crowding along cytoskeletal filaments depend on the competition of motors for their binding sites. We propose two models in which finite processive motor proteins actively advance along cytoskeletal filaments and are continuously exchanged with the motor pool. We first look at homogeneous reservoirs and then examine the effects of free motor diffusion in the surrounding medium. We consider as a reference situation recent in vitro experimental setups of kinesin-8 motors binding and moving along microtubule filaments in a flow chamber. We investigate how the crowding of linear motor proteins moving on a filament can be regulated by the balance between supply (concentration of motor proteins in the flow chamber) and demand (total number of polymerised tubulin heterodimers). We present analytical results for the density profiles of bound motors, the reservoir depletion, and propose novel phase diagrams that present the formation of jams of motor proteins on the filament as a function of two tuneable experimental parameters: the motor protein concentration and the concentration of tubulins polymerized into cytoskeletal filaments. Extensive numerical simulations corroborate the analytical results for parameters in the experimental range and also address the effects of diffusion of motor proteins in the reservoir.

q-bio.SC↗

arXiv2014

Anomalous transport of subdiffusing cargos by single kinesin motors: the role of mechanochemical coupling and anharmonicity of tether

Here we generalize our previous model of molecular motors trafficking subdiffusing cargos in viscoelastic cytosol by (i) including mechanochemical coupling between cyclic conformational fluctuations of the motor protein driven by the reaction of ATP hydrolysis and its translational motion within the simplest two-state model of hand-over-hand motion of kinesin, and also (ii) by taking into account the anharmonicity of the tether between the motor and cargo (its maximally possible extension length). It is shown that the major earlier results such as occurrence of normal versus anomalous transport depending on the amplitude of binding potential, cargo size and the motor turnover frequency not only survive in this more realistic model, but the results also look very similar for the correspondingly adjusted parameters. However, this more realistic model displays a substantially larger thermodynamic efficiency due to a bidirectional mechanochemical coupling. For realistic parameters, the maximal thermodynamic efficiency can be transiently about 50% as observed for kinesins, and even larger, surprisingly also in a novel strongly anomalous (sub)transport regime, where the motor enzymatic turnovers become also anomalously slow and cannot be characterized by a turnover rate. Here anomalously slow dynamics of the cargo enforces anomalously slow cyclic kinetics of the motor protein.

physics.bio-ph↗

arXiv2015

Role of dynamic capsomere supply for viral capsid self-assembly

Many viruses rely on the self-assembly of their capsids to protect and transport their genomic material. For many viral systems, in particular for human viruses like hepatitis B, adeno or human immunodeficiency virus, that lead to persistent infections, capsomeres are continuously produced in the cytoplasm of the host cell while completed capsids exit the cell for a new round of infection. Here we use coarse-grained Brownian dynamics simulations of a generic patchy particle model to elucidate the role of the dynamic supply of capsomeres for the reversible self-assembly of empty T1 icosahedral virus capsids. We find that for high rates of capsomere influx only a narrow range of bond strengths exists for which a steady state of continuous capsid production is possible. For bond strengths smaller and larger than this optimal value, the reaction volume becomes crowded by small and large intermediates, respectively. For lower rates of capsomere influx a broader range of bond strengths exists for which a steady state of continuous capsid production is established, although now the production rate of capsids is smaller. Thus our simulations suggest that the importance of an optimal bond strength for viral capsid assembly typical for in vitro conditions can be reduced by the dynamic influx of capsomeres in a cellular environment.

q-bio.SC↗

arXiv2014

Coherent regulation in yeast cell cycle network

We define a measure of coherent activity for gene regulatory networks, a property that reflects the unity of purpose between the regulatory agents with a common target. We propose that such harmonious regulatory action is desirable under a demand for energy efficiency and may be selected for under evolutionary pressures. We consider two recent models of the cell-cycle regulatory network of the budding yeast, Saccharomyces cerevisiae, as a case study and calculate their degree of coherence. A comparison with random networks of similar size and composition reveals that the yeast's cell-cycle regulation is wired to yield and exceptionally high level of coherent regulatory activity. We also investigate the mean degree of coherence as a function of the network size, connectivity and the fraction of repressory/activatory interactions.

q-bio.QM↗

arXiv2015

Mechanical properties of branched actin filaments

Cells moving on a two dimensional substrate generate motion by polymerizing actin filament networks inside a flat membrane protrusion. New filaments are generated by branching off existing ones, giving rise to branched network structures. We investigate the force-extension relation of branched filaments, grafted on an elastic structure at one end and pushing with the free ends against the leading edge cell membrane. Single filaments are modeled as worm-like chains, whose thermal bending fluctuations are restricted by the leading edge cell membrane, resulting in an effective force. Branching can increase the stiffness considerably; however the effect depends on branch point position and filament orientation, being most pronounced for intermediate tilt angles and intermediate branch point positions. We describe filament networks without cross-linkers to focus on the effect of branching. We use randomly positioned branch points, as generated in the process of treadmilling, and orientation distributions as measured in lamellipodia. These networks reproduce both the weak and strong force response of lamellipodia as measured in force-velocity experiments. We compare properties of branched and unbranched networks. The ratio of the network average of the force per branched filament to the average force per unbranched filament depends on the orientation distribution of the filaments. The ratio exhibits compression dependence and may go up to about 4.5 in networks with a narrow orientation distribution. With orientation distributions measured in lamellipodia, it is about two and essentially independent from network compression, graft elasticity and filament persistence length.

physics.bio-ph↗

arXiv2015

Facilitated diffusion framework for transcription factor search with conformational changes

Cellular responses often require the fast activation or repression of specific genes, which depends on Transcription Factors (TFs) that have to quickly find the promoters of these genes within a large genome. Transcription Factors (TFs) search for their DNA promoter target by alternating between bulk diffusion and sliding along the DNA, a mechanism known as facilitated diffusion. We study a facilitated diffusion framework with switching between three search modes: a bulk mode and two sliding modes triggered by conformational changes between two protein conformations. In one conformation (search mode) the TF interacts unspecifically with the DNA backbone resulting in fast sliding. In the other conformation (recognition mode) it interacts specifically and strongly with DNA base pairs leading to slow displacement. From the bulk, a TF associates with the DNA at a random position that is correlated with the previous dissociation point, which implicitly is a function of the DNA structure. The target affinity depends on the conformation. We derive exact expressions for the mean first passage time (MFPT) to bind to the promoter and the conditional probability to bind before detaching when arriving at the promoter site. We systematically explore the parameter space and compare various search scenarios. We compare our results with experimental data for the dimeric Lac repressor search in E.Coli bacteria. We find that a coiled DNA conformation is absolutely necessary for a fast MFPT. With frequent spontaneous conformational changes, a fast search time is achieved even when a TF becomes immobilized in the recognition state due to the specific bindings. We find a MFPT compatible with experimental data in presence of a specific TF-DNA interaction energy that has a Gaussian distribution with a large variance.

q-bio.SC↗

arXiv2014

Pearling instability of membrane tubes driven by curved proteins and actin polymerization

Membrane deformation inside living cells is crucial for the proper shaping of various intracellular organelles and is necessary during the fission/fusion processes that allow membrane recycling and transport (e.g. endocytosis). Proteins that induce membrane curvature play a key role in such processes, mostly by adsorbing to the membrane and forming a scaffold that deforms the membrane according to the curvature of the proteins. In this paper we explore the possibility of membrane tube destabilisation through a pearling mechanism enabled by the combined effects of the adsorbed curved proteins and the actin polymerization they may recruit. The pearling instability can furthermore serve as the initiation for fission of the tube into vesicles. We find that adsorbed proteins are more likely to stabilise the tubes, while the actin polymerization can provide the additional constrictive force needed for the robust instability. We discuss the relevance of the theoretical results to in-vivo and in-vitro experiments.

physics.bio-ph↗

arXiv2015

Enzyme oscillation can enhance the thermodynamic efficiency of cellular metabolism: Consequence of anti-phase coupling between reaction flux and affinity

Cells generally convert nutrient resources to useful products via energy transduction. Accordingly, the thermodynamic efficiency of this conversion process is one of the most essential characteristics of living organisms. However, although these processes occur under conditions of dynamic metabolism, most studies of cellular thermodynamic efficiency have been restricted to examining steady states; thus, the relevance of dynamics to this efficiency has not yet been elucidated. Here, we develop a simple model of metabolic reactions with anabolism-catabolism coupling catalysed by enzymes. Through application of external oscillation in the enzyme abundances, the thermodynamic efficiency of metabolism was found to be improved. This result is in strong contrast with that observed in the oscillatory input, in which the efficiency always decreased with oscillation. This improvement was effectively achieved by separating the anabolic and catabolic reactions, which tend to disequilibrate each other, and taking advantage of the temporal oscillations so that each of the antagonistic reactions could progress near equilibrium. In this case, anti-phase oscillation between the reaction flux and chemical affinity through oscillation of enzyme abundances is essential. This improvement was also confirmed in a model capable of generating autonomous oscillations in enzyme abundances. Finally, the possible relevance of the improvement in thermodynamic efficiency is discussed with respect to the potential for manipulation of metabolic oscillations in microorganisms.

physics.bio-ph↗

arXiv2016

Effects of 3D Geometries on Cellular Gradient Sensing and Polarization

During cell migration, cells become polarized, change their shape, and move in response to various internal and external cues. Cell polarization is defined through the spatio-temporal organization of molecules such as PI3K or small GTPases, and is determined by intracellular signaling networks. It results in directional forces through actin polymerization and myosin contractions. Many existing mathematical models of cell polarization are formulated in terms of reaction-diffusion systems of interacting molecules, and are often defined in one or two spatial dimensions. In this paper, we introduce a 3D reaction-diffusion model of interacting molecules in a single cell, and find that cell geometry has an important role affecting the capability of a cell to polarize, or change polarization when an external signal changes direction. Our results suggest a geometrical argument why more roundish cells can repolarize more effectively than cells which are elongated along the direction of the original stimulus, and thus enable roundish cells to turn faster, as has been observed in experiments. On the other hand, elongated cells preferentially polarize along their main axis even when a gradient stimulus appears from another direction. Furthermore, our 3D model can accurately capture the effect of binding and unbinding of important regulators of cell polarization to and from the cell membrane. This spatial separation of membrane and cytosol, not possible to capture in 1D or 2D models, leads to marked differences of our model from comparable lower-dimensional models.

physics.bio-ph↗

arXiv2016

Theory on the mechanism of site-specific DNA-protein interactions in the presence of traps

The speed of site-specific binding of transcription factor (TFs) proteins with genomic DNA seems to be strongly retarded by the randomly occurring sequence traps. Traps are those DNA sequences sharing significant similarity with the original specific binding sites. It is an intriguing question how the naturally occurring TFs and their specific binding sites are designed to manage the retarding effects of such randomly occurring traps. We develop a simple random walk model on the site-specific binding of TFs with genomic DNA in the presence of sequence traps. Our dynamical model predicts that (a) the retarding effects of traps will be minimum when the traps are arranged around the specific binding site such that there is a negative correlation between the binding strength of TFs with traps and the distance of traps from the specific binding site and (b) the retarding effects of sequence traps can be appeased by the condensed conformational state of DNA. Our computational analysis results on the distribution of sequence traps around the putative binding sites of various TFs in mouse and human genome clearly agree well the theoretical predictions. We propose that the distribution of traps can be used as an additional metric to efficiently identify the specific binding sites of TFs on genomic DNA.

q-bio.SC↗

arXiv2016

Spatial Organization of the Cytoskeleton enhances Cargo Delivery to Specific Target Areas on the Plasma Membrane of Spherical Cells

Intracellular transport is vital for the proper functioning and survival of a cell. Cargo (proteins, vesicles, organelles, etc.) is transferred from its place of creation to its target locations via molecular motor assisted transport along cytoskeletal filaments. The transport efficiency is strongly affected by the spatial organization of the cytoskeleton, which constitutes an inhomogeneous, complex network. In cells with a centrosome microtubules grow radially from the central microtubule organizing center towards the cell periphery whereas actin filaments form a dense meshwork, the actin cortex, underneath the cell membrane with a broad range of orientations. The emerging ballistic motion along filaments is frequently interrupted due to constricting intersection nodes or cycles of detachment and reattachment processes in the crowded cytoplasm. In order to investigate the efficiency of search strategies established by the cell's specific spatial organization of the cytoskeleton we formulate a random velocity model with intermittent arrest states. With extensive computer simulations we analyze the dependence of the mean first passage times for narrow escape problems on the structural characteristics of the cytoskeleton, the motor properties and the fraction of time spent in each state. We find that an inhomogeneous architecture with a small width of the actin cortex constitutes an efficient intracellular search strategy.

physics.bio-ph↗