On Estimation of a Viral Protein Diffusion Constant on the Curved Intracellular ER Surface

Knodel, Markus M.; Nägel, Arne; Reiter, Sebastian; Rupp, Martin; Vogel, Andreas; Lampe, M.; Targett-Adams, Paul; Herrmann, Eva; Wittum, Gabriel

doi:10.1007/978-3-319-24633-8_41

Cited by 7 publications

(16 citation statements)

References 27 publications

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“…Necessary future improvements are to use realistic values for the parameters of the model, and we are already working on this aspect. Recently, we estimated the diffusion constant of NS5a at the surface of the ER based on experimental FRAP time series data [35,36,37]. The value could be incorporated into our model; however, this only makes sense once there is also a perspective to get experimental data for at least some of the other parameters.…”

Section: Discussionmentioning

confidence: 99%

“…Section 2.2), labeled for the ER surface (calnexin marker) and for the MWs (dsRNA marker). Based on these z-stacks, we used the reconstructed various realistic ER surfaces as described previously [35,36,37] with the aid of NeuRA2 [35,36,46,47]. (For a brief overview over the reconstruction procedure, we refer to Appendix H.)…”

Section: Materials Methods and Modelsmentioning

confidence: 99%

“…However, due to a lack of adequate parameters for the diffusion–reaction equations, the model is more qualitative than quantitative. Therefore, we also built up a modeling framework to estimate the diffusion constant of the HCV NS5A viral protein on the ER surface [35,36,37]. Overall, our previous work on modeling the HCV RNA replication cycle [34] and first spatial parameter estimation [35,36,37] are likely the first attempts in the literature to establish a fully spatiotemporally resolved biophysical description of virus dynamics at an intracellular level.…”

Section: Introductionmentioning

confidence: 99%

“…Our model was evaluated using the simulation platform UG4 within a Finite Volume method (FV) [39,40]. Using fast multigrid solvers [41], our in silico model was evaluated on fast, massively parallel supercomputers [37]. Despite the more realistic approach and extension of the previous models, most of the parameters are still defined heuristically.…”

Section: Introductionmentioning

confidence: 99%

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Advanced Hepatitis C Virus Replication PDE Models within a Realistic Intracellular Geometric Environment

Knodel

Targett-Adams

Grillo

et al. 2019

IJERPH

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The hepatitis C virus (HCV) RNA replication cycle is a dynamic intracellular process occurring in three-dimensional space (3D), which is difficult both to capture experimentally and to visualize conceptually. HCV-generated replication factories are housed within virus-induced intracellular structures termed membranous webs (MW), which are derived from the Endoplasmatic Reticulum (ER). Recently, we published 3D spatiotemporal resolved diffusion–reaction models of the HCV RNA replication cycle by means of surface partial differential equation (sPDE) descriptions. We distinguished between the basic components of the HCV RNA replication cycle, namely HCV RNA, non-structural viral proteins (NSPs), and a host factor. In particular, we evaluated the sPDE models upon realistic reconstructed intracellular compartments (ER/MW). In this paper, we propose a significant extension of the model based upon two additional parameters: different aggregate states of HCV RNA and NSPs, and population dynamics inspired diffusion and reaction coefficients instead of multilinear ones. The combination of both aspects enables realistic modeling of viral replication at all scales. Specifically, we describe a replication complex state consisting of HCV RNA together with a defined amount of NSPs. As a result of the combination of spatial resolution and different aggregate states, the new model mimics a cis requirement for HCV RNA replication. We used heuristic parameters for our simulations, which were run only on a subsection of the ER. Nevertheless, this was sufficient to allow the fitting of core aspects of virus reproduction, at least qualitatively. Our findings should help stimulate new model approaches and experimental directions for virology.

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Section: Discussionmentioning

confidence: 99%

Section: Materials Methods and Modelsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Advanced Hepatitis C Virus Replication PDE Models within a Realistic Intracellular Geometric Environment

Knodel

Targett-Adams

Grillo

et al. 2019

IJERPH

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“…We thank Konstantinos Xylouris (G-CSC) for very fruitful discussions on the evaluation of the simulation results, Martin Rupp (G-CSC) for very friendly technical support with respect to the implementation of the solvers, Ranjita Dutta-Roy (Karolinska Institute, Stockholm, Sweden) for profound explanations of FRAP experimental setup and data analysis, Stefan Groote (University of Tartu, Estonia) for proof reading the manuscript and very helpful hints, Tobias Denninger (Heidelberg, Germany) for very stimulating discussions about spatial resolution within computational biophysics, Alfio Grillo (Politecnico di Torino, Italy) and Jürgen Vollmer (MPI Göttingen, Germany) for very stimulating discussions about the subject, and Wouter van Beerendonk (Huygens SVI, Netherlands) for his very friendly support in Huygens usage, backgrounds, and licensing. The HLRS Stuttgart is acknowledged for the supplied computing time on the Hermit and Hornet super computers [ 90 ], and Michael Lampe for very friendly technical support on the G-CSC cesari cluster. The authors acknowledge the Goethe Universität Frankfurt for general support and computational resources and the Politecnico di Torino for general support.…”

Section: Acknowledgmentsmentioning

confidence: 99%

Quantitative Analysis of Hepatitis C NS5A Viral Protein Dynamics on the ER Surface

Knodel

Nägel

Reiter

et al. 2018

Viruses

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Exploring biophysical properties of virus-encoded components and their requirement for virus replication is an exciting new area of interdisciplinary virological research. To date, spatial resolution has only rarely been analyzed in computational/biophysical descriptions of virus replication dynamics. However, it is widely acknowledged that intracellular spatial dependence is a crucial component of virus life cycles. The hepatitis C virus-encoded NS5A protein is an endoplasmatic reticulum (ER)-anchored viral protein and an essential component of the virus replication machinery. Therefore, we simulate NS5A dynamics on realistic reconstructed, curved ER surfaces by means of surface partial differential equations (sPDE) upon unstructured grids. We match the in silico NS5A diffusion constant such that the NS5A sPDE simulation data reproduce experimental NS5A fluorescence recovery after photobleaching (FRAP) time series data. This parameter estimation yields the NS5A diffusion constant. Such parameters are needed for spatial models of HCV dynamics, which we are developing in parallel but remain qualitative at this stage. Thus, our present study likely provides the first quantitative biophysical description of the movement of a viral component. Our spatio-temporal resolved ansatz paves new ways for understanding intricate spatial-defined processes central to specfic aspects of virus life cycles.

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Multigrid analysis of spatially resolved hepatitis C virus protein simulations

Knodel

Nägel

Reiter

et al. 2015

Comput. Visual Sci.

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On Estimation of a Viral Protein Diffusion Constant on the Curved Intracellular ER Surface

Cited by 7 publications

References 27 publications

Advanced Hepatitis C Virus Replication PDE Models within a Realistic Intracellular Geometric Environment

Advanced Hepatitis C Virus Replication PDE Models within a Realistic Intracellular Geometric Environment

Quantitative Analysis of Hepatitis C NS5A Viral Protein Dynamics on the ER Surface

Multigrid analysis of spatially resolved hepatitis C virus protein simulations

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