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At least 145 records · Page 8Linked to original sources
arXiv2011

Computational modeling of differences in the quorum sensing induced luminescence phenotypes of \textit{Vibrio harveyi} and \textit{Vibrio cholerae}

\textit{Vibrio harveyi} and \textit{Vibrio cholerae} have quorum sensing pathways with similar design and highly homologous components including multiple small RNAs (sRNAs). However, the associated luminescence phenotypes of strains with sRNA deletions differ dramatically: in \textit{V. harveyi}, the sRNAs act additively; however, in \textit{V. cholerae}, the sRNAs act redundantly. Furthermore, there are striking differences in the luminescence phenotypes for different pathway mutants in \textit{V. harveyi} and \textit{V. cholerae}. However these differences have not been connected with the observed differences for the sRNA deletion strains in these bacteria. In this work, we present a model for quorum sensing induced luminescence phenotypes focusing on the interactions of multiple sRNAs with target mRNA. Within our model, we find that one key parameter -- the fold-change in protein concentration necessary for luminescence activation -- can control whether the sRNAs appear to act additively or redundantly. For specific parameter choices, we find that differences in this key parameter can also explain hitherto unconnected luminescence phenotypes differences for various pathway mutants in \textit{V. harveyi} and \textit{V. cholerae}. The model can thus provide a unifying explanation for observed differences in luminescence phenotypes and can also be used to make testable predictions for future experiments.

q-bio.MN↗
arXiv2011

Enzyme sharing as a cause of multistationarity in signaling systems

Multistationarity in biological systems is a mechanism of cellular decision making. In particular, signaling pathways regulated by protein phosphorylation display features that facilitate a variety of responses to different biological inputs. The features that lead to multistationarity are of particular interest to determine as well as the stability properties of the steady states. In this paper we determine conditions for the emergence of multistationarity in small motifs without feedback that repeatedly occur in signaling pathways. We derive an explicit mathematical relationship between the concentration of a chemical species at steady state and a conserved quantity of the system such as the total amount of substrate available. We show that the relation determines the number of steady states and provides a necessary condition for a steady state to be stable, that is, to be biologically attainable. Further, we identify characteristics of the motifs that lead to multistationarity, and extend the view that multistationarity in signaling pathways arises from multisite phosphorylation. Our approach relies on mass-action kinetics and the conclusions are drawn in full generality without resorting to simulations or random generation of parameters. The approach is extensible to other systems.

q-bio.SC↗
arXiv2011

Insights into the mechanisms of electromediated gene delivery and application to the loading of giant vesicles with negatively charged macromolecules

We present experimental results regarding the electrotransfer of plasmid DNA into phosphatidylcholine giant unilamellar vesicles (GUVs). Our observations indicate that a direct entry is the predominant mechanism of electrotransfer. A quantitative analysis of the DNA concentration increments inside the GUVs is also performed, and we find that our experimental data are very well described by a simple theoretical model in which DNA entry is mostly driven by electrophoresis. Our theoretical framework allows for the prediction of the amount of transfered DNA as a function of the electric field parameters, and thus paves the way towards a novel method for encapsulating with high efficiency not only DNA, but any negatively charged macromolecule into GUVs.

physics.bio-ph↗
arXiv2011

Electromediated formation of DNA complexes with cell membranes and its consequences for gene delivery

Electroporation is a physical method to induce the uptake of therapeutic drugs and DNA, by eukaryotic cells and tissues. The phenomena behind electro-mediated membrane permeabilization to plasmid DNA have been shown to be significantly more complex than those for small molecules. Small molecules cross the permeabilized membrane by diffusion whereas plasmid DNA first interacts with the electropermeabilized part of the cell surface, forming localized aggregates. The dynamics of this process is still poorly understood because direct observations have been limited to scales of the order of seconds. Here, cells are electropermeabilized in the presence of plasmid DNA and monitored with a temporal resolution of 2 ms. This allows us to show that during the first pulse application, plasmid complexes, or aggregates, start to form at distinct sites on the cell membrane. FRAP measurements show that the positions of these sites are remarkably immobile during the application of further pluses. A theoretical model is proposed to explain the appearance of distinct interaction sites, the quantitative increase in DNA and also their immobility leading to a tentative explanation for the success of electro-mediated gene delivery.

physics.bio-ph↗
arXiv2011

Crosstalk between non-processive myosin motors mediated by the actin filament elasticity

Many biological processes involve the action of molecular motors that interact with the cell cytoskeleton. Some processes, such as the transport of cargoes is achieved mainly by the action of individual motors. Other, such as cell motility and division, require the cooperative work of many motors. Collective motor dynamics can be quite complex and unexpected. One beautiful example is the bidirectional ("back and forth") motion of filaments which is induced when the motors within a group exert forces in opposite directions. This review tackles the puzzle emerging from a recent experimental work in which it has been shown that the characteristic reversal times of the bidirectional motion are practically independent of the number of motors. This result is in a striking contradiction with existing theoretical models that predict an exponential growth of the reversal times with the size of the system. We argue that the solution to this puzzle may be the crosstalk between the motors which is mediated by the elastic tensile stress that develops in the cytoskeleton track. The crosstalk does not directly correlate the attachment and detachment of the motors, which work independently of each other. However, it highly accelerates their detachments by making the detachment rates system size dependent.

physics.bio-ph↗
arXiv2011

Relative velocity of sliding of microtubules by the action of Kinesin-5

Kinesin-5, also known as Eg5 in vertebrates is a processive motor with 4 heads, which moves on filamentous tracks called microtubules. The basic function of Kinesin-5 is to slide apart two anti-parallel microtubules by simultaneously walking on both the microtubules. We develop an analytical expression for the steady-state relative velocity of this sliding in terms of the rates of attachments and detachments of motor heads with the ATPase sites on the microtubules. We first analyse the motion of one pair of motor heads on one microtubule and then couple it to the motion of the other pair of motor heads of the same motor on the second microtubule to get the relative velocity of sliding.

physics.bio-ph↗
arXiv2011

Direct measurement of the correlated dynamics of the protein-backbone and proximal waters of hydration in mechanically strained elastin

We report on the direct measurement of the correlation times of the protein backbone carbons and proximal waters of hydration in mechanically strained elastin by nuclear magnetic resonance methods. The experimental data indicate a decrease in the correlation times of the carbonyl carbons as the strain on the biopolymer is increased. These observations are in good agreement with short 4ns molecular dynamics simulations of (VPGVG)3, a well studied mimetic peptide of elastin. The experimental results also indicate a reduction in the correlation time of proximal waters of hydration with increasing strain applied to the elastomer. A simple model is suggested that correlates the increase in the motion of proximal waters of hydration to the increase in frequency of libration of the protein backbone that develops with increasing strain. Together, the reduction in the protein entropy accompanied with the increase in entropy of the proximal waters of hydration with increasing strain, support the notion that the source of elasticity is driven by an entropic mechanism arising from the change in entropy of the protein backbone.

physics.bio-ph↗
arXiv2011

Dynamic control of catalysis within biological cells

We develop a theory of enzyme catalysis within biological cells where the substrate concentration [S](t) is time dependent, in contrast to the Michaelis-Menten theory that assumes a steady state. We find that the time varying concentration can combine, in a non-linear way, with the ruggedness of the free energy landscape of enzymes (discovered both in single molecule studies and in simulations) to provide a highly efficient switch (or, bifurcation) between two catalytically active states, at a critical substrate concentration. This allows a dynamic control of product synthesis in cell.

cond-mat.stat-mech↗
arXiv2011

Dynamic modeling of gene expression in prokaryotes: application to glucose-lactose diauxie in Escherichia coli

Coexpression of genes or, more generally, similarity in the expression profiles poses an unsurmountable obstacle to inferring the gene regulatory network (GRN) based solely on data from DNA microarray time series. Clustering of genes with similar expression profiles allows for a course-grained view of the GRN and a probabilistic determination of the connectivity among the clusters. We present a model for the temporal evolution of a gene cluster network which takes into account interactions of gene products with genes and, through a non-constant degradation rate, with other gene products. The number of model parameters is reduced by using polynomial functions to interpolate temporal data points. In this manner, the task of parameter estimation is reduced to a system of linear algebraic equations, thus making the computation time shorter by orders of magnitude. To eliminate irrelevant networks, we test each GRN for stability with respect to parameter variations, and impose restrictions on its behavior near the steady state. We apply our model and methods to DNA microarray time series' data collected on Escherichia coli during glucose-lactose diauxie and infer the most probable cluster network for different phases of the experiment.

q-bio.MN↗
arXiv2012

Positive feedback and temperature mediated molecular switch controls differential gene regulation in Bordetella pertussis

Based on the phosphorelay kinetics operative within BvgAS two component system we propose a mathematical framework for signal transduction and gene regulation of phenotypic phases in Bordetella pertussis. The proposed model identifies a novel mechanism of transcriptional interference between two promoters present in the bvg locus. To understand the system behavior under elevated temperature, the developed model has been studied in two different ways. First, a quasi-steady state analysis has been carried out for the two component system, comprising of sensor BvgS and response regulator BvgA. The quasi-steady state analysis reveals temperature induced sharp molecular switch, leading to amplification in the output of BvgA. Accumulation of a large pool of BvgA thus results into differential regulation of the downstream genes, including the gene encoding toxin. Numerical integration of the full network kinetics is then carried out to explore time dependent behavior of different system components, that qualitatively capture the essential features of experimental results performed in vivo. Furthermore, the developed model has been utilized to study mutants that are impaired in their ability to phosphorylate the transcription factor, BvgA, of the signaling network.

q-bio.MN↗
arXiv2011

Clusters of proteins in bio-membranes: insights into the roles of interaction potential shapes and of protein diversity

It has recently been proposed that proteins embedded in lipidic bio-membranes can spontaneously self-organize into stable small clusters, or membrane nano-domains, due to the competition between short-range attractive and longer-range repulsive forces between proteins, specific to these systems. In this paper, we carry on our investigation, by Monte Carlo simulations, of different aspects of cluster phases of proteins in bio-membranes. First, we compare different long-range potentials (including notably three-body terms) to demonstrate that the existence of cluster phases should be quite generic. Furthermore, a real membrane contains hundreds of different protein species that are far from being randomly distributed in these nano-domains. We take this protein diversity into account by modulating protein-protein interaction potentials both at short and longer range. We confirm theoretical predictions in terms of biological cluster specialization by deciphering how clusters recruit only a few protein species. In this respect, we highlight that cluster phases can turn out to be an advantage at the biological level, for example by enhancing the cell response to external stimuli.

cond-mat.soft↗
arXiv2012

Jamming of molecular motors as a tool for transport cargos along microtubules

The hopping model for cargo transport by molecular motors introduced in Refs. goldman1, goldman2, is extended here in order to incorporate the movement of cargo-motor complexes. In this context, hopping process expresses the possibility for cargo to be exchanged between neighbor motors at a microtubule where the transport takes place. Jamming of motors is essential for cargos to execute long-range movement in this way. Results from computer simulations performed using the extended model indicate that cargo may execute bidirectional movement in the presence of motors of a single polarity, confirming previous analytical results. Moreover, these results suggest the existence of a balance between cargo hopping and the movement of the complex that may control the efficiency of cargo transfer and cargo delivering. Considerations about the energy involved in the transport process show that the model presented here offers a considerable advantage over other models in the literature for which cargo movement is restricted to the movement of cargo-motor complexes.

q-bio.SC↗
arXiv2011

Realistic extensions of a Brownian ratchet for protein translocation

We study a model for the translocation of proteins across membranes through a nanopore using a ratcheting mechanism. When the protein enters the nanopore it diffuses in and out of the pore according to a Brownian motion. Moreover, it is bound by ratcheting molecules which hinder the diffusion of the protein out of the nanopore, i.e. the Brownian motion is reflected such that no ratcheting molecule exits the pore. New ratcheting molecules bind at rate gamma. Extending our previous approach (Depperschmidt and Pfaffelhuber, 2010) we allow the ratcheting molecules to dissociate (at rate delta) from the protein (Model I). We also provide an approximate model (Model II) which assumes a Poisson equilibrium of ratcheting molecules on one side of the current reflection boundary. Using analytical methods and simulations we show that the speed of both models are approximately the same. Our analytical results on Model II give the speed of translocation by means of a solution of an ordinary differential equation.

math.PR↗
arXiv2011

Directed transport in equilibrium : analysis of the dimer model with inertial terms

We have previously shown an analysis of our dimer model in the over-damped regime to show directed transport in equilibrium. Here we analyze the full model with inertial terms present to establish the same result. First we derive the Fokker-Planck equation for the system following a Galilean transformation to show that a uniformly translating equilibrium distribution is possible. Then, we find out the velocity selection for the centre of mass motion using that distribution on our model. We suggest generalization of our calculations for soft collision potentials and indicate to interesting situation with possibility of oscillatory non-equilibrium state within equilibrium.

cond-mat.stat-mech↗
arXiv2011

Equilibrium insertion of nanoscale objects into phospholipid bilayers

Certain membrane proteins, peptides, nanoparticles and nanotubes have rigid structure and fixed shape. They are often viewed as spheres and cylinders with certain surface properties. Single Chain Mean Field theory is used to model the equilibrium insertion of nanoscale spheres and rods into the phospholipid bilayer. The equilibrium structures and the resulting free energies of the nano-objects in the bilayer allow to distinguish different orientations in the bilayer and estimate the energy barrier of insertion.

physics.bio-ph↗
arXiv2011

Modeling the early steps of cytoplasmic trafficking in viral infection and gene delivery

Gene delivery of nucleic acid to the cell nucleus is a fundamental step in gene therapy. In this review of modeling drug and gene delivery, we focus on the particular stage of plasmid DNA or virus cytoplasmic trafficking. A challenging problem is to quantify the success of this limiting stage. We present some models and simulations of plasmid trafficking and of the limiting phase of DNA-polycation escape from an endosome and discuss virus cytoplasmic trafficking. The models can be used to assess the success of viral escape from endosomes, to quantify the early step of viral-cell infection, and to propose new simulation tools for designing new hybrid-viruses as synthetic vectors.

q-bio.SC↗
arXiv2011

Exact Analysis of Intrinsic Qualitative Features of Phosphorelays using Mathematical Models

Phosphorelays are a class of signaling mechanisms used by cells to respond to changes in their environment. Phosphorelays (of which two-component systems constitute a special case) are particularly abundant in prokaryotes and have been shown to be involved in many fundamental processes such as stress response, osmotic regulation, virulence, and chemotaxis. We develop a general model of phosphorelays extending existing models of phosphorelays and two-component systems. We analyze the model analytically under the assumption of mass-action kinetics and prove that a phosphorelay has a unique stable steady-state. Furthermore, we derive explicit functions relating stimulus to the response in any layer of a phosphorelay and show that a limited degree of ultrasensitivity (the ability to respond to changes in stimulus in a switch-like manner) in the bottom layer of a phosphorelay is an intrinsic feature which does not depend on any reaction rates or substrate amounts. On the other hand, we show how adjusting reaction rates and substrate amounts may lead to higher degrees of ultrasensitivity in intermediate layers. The explicit formulas also enable us to prove how the response changes with alterations in stimulus, kinetic parameters, and substrate amounts. Aside from providing biological insight, the formulas may also be used to avoid time-consuming simulations in numerical analyses and simulations.

q-bio.MN↗