Intracellular transport driven by cytoskeletal motors: General mechanisms and defects

Cells are strongly out-of-equilibrium systems driven by continuous energy supply. They carry out many vital functions requiring active transport of various ingredients and organelles, some being small, others being large. The cytoskeleton, composed of three types of filaments, determines the shape of the cell and plays a role in cell motion. It also serves as a road network for the so-called cytoskeletal motors. These molecules can attach to a cytoskeletal filament, perform directed motion, possibly carrying along some cargo, and then detach. It is a central issue to understand how intracellular transport driven by molecular motors is regulated, in particular because its breakdown is one of the signatures of some neuronal diseases like the Alzheimer. We give a survey of the current knowledge on microtubule based intracellular transport. We first review some biological facts obtained from experiments, and present some modeling attempts based on cellular automata. We start with background knowledge on the original and variants of the TASEP (Totally Asymmetric Simple Exclusion Process), before turning to more application oriented models. After addressing microtubule based transport in general, with a focus on in vitro experiments, and on cooperative effects in the transportation of large cargos by multiple motors, we concentrate on axonal transport, because of its relevance for neuronal diseases. It is a challenge to understand how this transport is organized, given that it takes place in a confined environment and that several types of motors moving in opposite directions are involved. We review several features that could contribute to the efficiency of this transport, including the role of motor-motor interactions and of the dynamics of the underlying microtubule network. Finally, we discuss some still open questions.Comment: 74 pages, 43 figure

The Grand-Canonical Asymmetric Exclusion Process and the One-Transit Walk

The one-dimensional Asymmetric Exclusion Process (ASEP) is a paradigm for nonequilibrium dynamics, in particular driven diffusive processes. It is usually considered in a canonical ensemble in which the number of sites is fixed. We observe that the grand-canonical partition function for the ASEP is remarkably simple. It allows a simple direct derivation of the asymptotics of the canonical normalization in various phases and of the correspondence with One-Transit Walks recently observed by Brak et.al.Comment: Published versio

Maximizing Protein Translation Rate in the Ribosome Flow Model: the Homogeneous Case

Gene translation is the process in which intracellular macro-molecules, called ribosomes, decode genetic information in the mRNA chain into the corresponding proteins. Gene translation includes several steps. During the elongation step, ribosomes move along the mRNA in a sequential manner and link amino-acids together in the corresponding order to produce the proteins. The homogeneous ribosome flow model(HRFM) is a deterministic computational model for translation-elongation under the assumption of constant elongation rates along the mRNA chain. The HRFM is described by a set of n first-order nonlinear ordinary differential equations, where n represents the number of sites along the mRNA chain. The HRFM also includes two positive parameters: ribosomal initiation rate and the (constant) elongation rate. In this paper, we show that the steady-state translation rate in the HRFM is a concave function of its parameters. This means that the problem of determining the parameter values that maximize the translation rate is relatively simple. Our results may contribute to a better understanding of the mechanisms and evolution of translation-elongation. We demonstrate this by using the theoretical results to estimate the initiation rate in M. musculus embryonic stem cell. The underlying assumption is that evolution optimized the translation mechanism. For the infinite-dimensional HRFM, we derive a closed-form solution to the problem of determining the initiation and transition rates that maximize the protein translation rate. We show that these expressions provide good approximations for the optimal values in the n-dimensional HRFM already for relatively small values of n. These results may have applications for synthetic biology where an important problem is to re-engineer genomic systems in order to maximize the protein production rate

When is a bottleneck a bottleneck?

Bottlenecks, i.e. local reductions of capacity, are one of the most relevant scenarios of traffic systems. The asymmetric simple exclusion process (ASEP) with a defect is a minimal model for such a bottleneck scenario. One crucial question is "What is the critical strength of the defect that is required to create global effects, i.e. traffic jams localized at the defect position". Intuitively one would expect that already an arbitrarily small bottleneck strength leads to global effects in the system, e.g. a reduction of the maximal current. Therefore it came as a surprise when, based on computer simulations, it was claimed that the reaction of the system depends in non-continuous way on the defect strength and weak defects do not have a global influence on the system. Here we reconcile intuition and simulations by showing that indeed the critical defect strength is zero. We discuss the implications for the analysis of empirical and numerical data.Comment: 8 pages, to appear in the proceedings of Traffic and Granular Flow '1

Analyzing Linear Communication Networks using the Ribosome Flow Model

The Ribosome Flow Model (RFM) describes the unidirectional movement of interacting particles along a one-dimensional chain of sites. As a site becomes fuller, the effective entry rate into this site decreases. The RFM has been used to model and analyze mRNA translation, a biological process in which ribosomes (the particles) move along the mRNA molecule (the chain), and decode the genetic information into proteins. Here we propose the RFM as an analytical framework for modeling and analyzing linear communication networks. In this context, the moving particles are data-packets, the chain of sites is a one dimensional set of ordered buffers, and the decreasing entry rate to a fuller buffer represents a kind of decentralized backpressure flow control. For an RFM with homogeneous link capacities, we provide closed-form expressions for important network metrics including the throughput and end-to-end delay. We use these results to analyze the hop length and the transmission probability (in a contention access mode) that minimize the end-to-end delay in a multihop linear network, and provide closed-form expressions for the optimal parameter values

Physics of Transport and Traffic Phenomena in Biology: from molecular motors and cells to organisms

Traffic-like collective movements are observed at almost all levels of biological systems. Molecular motor proteins like, for example, kinesin and dynein, which are the vehicles of almost all intra-cellular transport in eukayotic cells, sometimes encounter traffic jam that manifests as a disease of the organism. Similarly, traffic jam of collagenase MMP-1, which moves on the collagen fibrils of the extracellular matrix of vertebrates, has also been observed in recent experiments. Traffic-like movements of social insects like ants and termites on trails are, perhaps, more familiar in our everyday life. Experimental, theoretical and computational investigations in the last few years have led to a deeper understanding of the generic or common physical principles involved in these phenomena. In particular, some of the methods of non-equilibrium statistical mechanics, pioneered almost a hundred years ago by Einstein, Langevin and others, turned out to be powerful theoretical tools for quantitaive analysis of models of these traffic-like collective phenomena as these systems are intrinsically far from equilibrium. In this review we critically examine the current status of our understanding, expose the limitations of the existing methods, mention open challenging questions and speculate on the possible future directions of research in this interdisciplinary area where physics meets not only chemistry and biology but also (nano-)technology.Comment: 33 page Review article, REVTEX text, 29 EPS and PS figure