title: Multiscale Modeling of Bacterial Chemotaxis
creator: Vladimirov, Nikita
subject: ddc-570
subject: 570 Life sciences
description: One of the central questions of modern systems biology is the role of microscopic parameters of a single cell in the behavior of a cell population. Multiscale models help to address this problem, allowing to understand population behavior from the information about single-cell molecular components and reactions. This goal requires models that are sufficiently detailed to capture central intracellular processes, but at the same time enable simulation of entire cell populations.  In this work a novel multiscale (hybrid) model is presented, which describes chemotactic Escherichia coli bacterium by a combination of heterogeneous mathematical approaches in one platform: rapid-equilibrium (algebraic) models, ordinary differential equations, and stochastic processes. The multiscale approach is based on time-scale separation of key reactions. The resulting model of chemotactic bacterium describes signal processing by mixed chemoreceptor clusters (MWC model), adaptation through methylation, running and tumbling of a cell with several flagellar motors. The model is implemented in a program RapidCell. It outperforms the present simulation software in reproducing the experimental data on pathway sensitivity, and simulates bacterial populations in a computationally efficient way. The model was used to investigate chemotaxis in different gradients. A theoretical analysis of the receptor cluster (MWC) model suggested a new, constant-activity type of gradient to systematically study chemotactic behavior of bacteria in silico. Using the unique properties of this gradient, it is shown that the optimal chemotaxis is observed in a narrow range of CheA kinase activity, where concentration of the response regulator CheYp falls into the operating range of flagellar motors. Simulations further confirm that the CheB phosphorylation feedback improves chemotactic efficiency in a number of gradients by shifting the average CheYp concentration to fit the motor operating range. Comparative simulations of motility in liquid and porous media suggest that adaptation time required for optimal chemotaxis depends on the medium. In liquid medium, the variability in adaptation times among cells  may be evolutionary favourable to ensure co-existence of subpopulations that will be optimally tactic in different gradients. However, in a porous medium (agar) such variability appears to be less important, because agar structure poses mainly negative selection, against subpopulations with low levels of adaptation enzymes. A detailed model of cell motion predicts existence of an additional mechanism of gradient navigation in E. coli. Based on the experimentally observed dependence of cell tumbling angle on the number of clockwise-rotating motors, the model suggests that not only the tumbling frequency, but also the angle of reorientation during a tumble depends on the swimming direction along the gradient. Although the difference in mean tumbling angles up and down the gradient predicted by the model is small, it results in a dramatic enhancement of the cellular drift velocity along the gradient. This result demonstrates a new level of optimization in E. coli chemotaxis, which arises from collective switching of several flagellar motors and a resulting fine tuning of tumbling angle. Similar strategy is likely to be used by other peritrichously flagellated bacteria, and indicates a yet another level of evolutionary optimization in bacterial chemotaxis. Concluding, multiscale models as the one presented here can be an important research instrument for understanding the cell behavior. They reflect the most important experimental knowledge about the biological system, and allow to carry out computational experiments of high complexity, which may be too complicated for experimental trials. Currently, there is abundant experimental data on signal transduction in living organisms, but there is no general mathematical framework to integrate heterogeneous models over the wide range of scales present in most biological systems. This thesis is a new stone in the work aimed to "bridge the scales" in biology.
date: 2009
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/10183/1/Thesis_full_bluelinks.pdf
identifier: DOI:10.11588/heidok.00010183
identifier: urn:nbn:de:bsz:16-opus-101831
identifier:   Vladimirov, Nikita  (2009) Multiscale Modeling of Bacterial Chemotaxis.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/10183/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng