Agent-based simulation of reactions in the crowded and structured intracellular environment: Influence of mobility and location of the reactants

<p>Abstract</p> <p>Background</p> <p>In this paper we apply a novel agent-based simulation method in order to model intracellular reactions in detail. The simulations are performed within a virtual cytoskeleton enriched with further crowding elements, which allows the analysis of molecular crowding effects on intracellular diffusion and reaction rates. The cytoskeleton network leads to a reduction in the mobility of molecules. Molecules can also unspecifically bind to membranes or the cytoskeleton affecting (i) the fraction of unbound molecules in the cytosol and (ii) furthermore reducing the mobility. Binding of molecules to intracellular structures or scaffolds can in turn lead to a microcompartmentalization of the cell. Especially the formation of enzyme complexes promoting metabolic channeling, e.g. in glycolysis, depends on the co-localization of the proteins.</p> <p>Results</p> <p>While the co-localization of enzymes leads to faster reaction rates, the reduced mobility decreases the collision rate of reactants, hence reducing the reaction rate, as expected. This effect is most prominent in diffusion limited reactions. Furthermore, anomalous diffusion can occur due to molecular crowding in the cell. In the context of diffusion controlled reactions, anomalous diffusion leads to fractal reaction kinetics. The simulation framework is used to quantify and separate the effects originating from molecular crowding or the reduced mobility of the reactants. We were able to define three factors which describe the effective reaction rate, namely <it>f ^diff</it>for the diffusion effect, <it>f ^volume</it>for the crowding, and <it>f ^access</it>for the reduced accessibility of the molecules.</p> <p>Conclusions</p> <p>Molecule distributions, reaction rate constants and structural parameters can be adjusted separately in the simulation allowing a comprehensive study of individual effects in the context of a realistic cell environment. As such, the present simulation can help to bridge the gap between <it>in vivo </it>and <it>in vitro </it>kinetics.</p

Multiscale modelling of vascular tumour growth in 3D: the roles of domain size & boundary condition

We investigate a three-dimensional multiscale model of vascular tumour growth, which couples blood flow, angiogenesis, vascular remodelling, nutrient/growth factor transport, movement of, and interactions between, normal and tumour cells, and nutrient-dependent cell cycle dynamics within each cell. In particular, we determine how the domain size, aspect ratio and initial vascular network influence the tumour's growth dynamics and its long-time composition. We establish whether it is possible to extrapolate simulation results obtained for small domains to larger ones, by constructing a large simulation domain from a number of identical subdomains, each subsystem initially comprising two parallel parent vessels, with associated cells and diffusible substances. We find that the subsystem is not representative of the full domain and conclude that, for this initial vessel geometry, interactions between adjacent subsystems contribute to the overall growth dynamics. We then show that extrapolation of results from a small subdomain to a larger domain can only be made if the subdomain is sufficiently large and is initialised with a sufficiently complex vascular network. Motivated by these results, we perform simulations to investigate the tumour's response to therapy and show that the probability of tumour elimination in a larger domain can be extrapolated from simulation results on a smaller domain. Finally, we demonstrate how our model may be combined with experimental data, to predict the spatio-temporal evolution of a vascular tumour

Multi-scale spatio-temporal modeling: lifelines of microorganisms in bioreactors and tracking molecules in cells. Biosystems Engineering II: Linking Cellular Networks

Abstract Agent-based models are rigorous tools for simulating the interactions of individual entities, such as organisms or molecules within cells and assessing their effects on the dynamic behavior of the system as a whole. In context with bioprocess and biosystems engineering there are several interesting and important applications. This contribution aims at introducing this strategy with the aid of two examples characterized by striking distinctions in the scale of the individual entities and the mode of their interactions. In the first example a structured-segregated model is applied to travel along the lifelines of single cells in the environment of a three-dimensional turbulent field of a stirred bioreactor. The modeling approach is based on an Euler-Lagrange formulation of the system. The strategy permits one to account for the heterogeneity present in real reactors in both the fluid and cellular phases, respectively. The individual response of the cells to local variations in the extracellular concentrations is pictured by a dynamically structured model of the key reactions of the central metabolism. The approach permits analysis of the lifelines of individual cells in space and time. The second application of the individual modeling approach deals with dynamic modeling of signal transduction pathways in individual cells. Usually signal transduction networks are portrayed as being wired together in a spatially defined manner. Living circuitry, however, is placed in highly malleable internal architecture. Creating a homogenous bag of molecules, a well-mixed system, the dynamic behavior of which is modeled with a set of ordinary differential equations is normally not valid. The dynamics of the MAP kinase and a steroid hormone pathway serve as examples to illustrate how single molecule tracking can be linked with the stochasticity of biochemical reactions, where diffusion and reaction occur in a probabilistic manner. The problem of hindered diffusion caused by macromolecular crowding is also taken into account

Stochastic Simulation of Signal Transduction: Impact of the Cellular Architecture on Diffusion

The transduction of signals depends on the translocation of signaling molecules to specific targets. Undirected diffusion processes play a key role in the bridging of spaces between different cellular compartments. The diffusion of the molecules is, in turn, governed by the intracellular architecture. Molecular crowding and the cytoskeleton decrease macroscopic diffusion. This article shows the use of a stochastic simulation method to study the effects of the cytoskeleton structure on the mobility of macromolecules. Brownian dynamics and single particle tracking were used to simulate the diffusion process of individual molecules through a model cytoskeleton. The resulting average effective diffusion is in line with data obtained in the in vitro and in vivo experiments. It shows that the cytoskeleton structure strongly influences the diffusion of macromolecules. The simulation method used also allows the inclusion of reactions in order to model complete signaling pathways in their spatio-temporal dynamics, taking into account the effects of the cellular architecture