 
Stochastic simulation of reactiondiffusion processes in molecular biology
Stochastic simulation of reactiondiffusion processes in molecular biology
The problem of high dimension is even more severe if the species are space dependent.
Then the cell domain in partitioned into voxels or subcompartments in a mesoscopic model
and the state of the system is defined by the copy number of the species in each voxel.
The molecules react with each other and diffuse to neighboring voxels.
The only computationally feasible
alternative is to simulate the system with a Monte Carlo method. A method to compute a trajectory has been developed for unstructured
meshes, for active transport, and for one dimensional structures embedded in 3D space based on Gillespie's Stochastic Simulation Algorithm.
An even more detailed model is microscopic simulation of single molecules. The Smoluchowski model for spherical molecules to react
with each other and diffuse in Brownian motion has been implemented efficiently using the the ideas in Green's Function Reaction Dynamics (GFRD)
by van Zon and ten Wolde.
The new position of a free molecule is sampled from a Gaussian distribution. For two molecules in the neighborhood of each other
their new relative position is determined by
a probability distribution satisfying the Smoluchowski equation.
The macrosopic model for the concentrations of the species is
the reactiondiffusion partial differential equation. Methods have been developed for the coupling of the
mesoscopic model with the macroscopic model and for the coupling of the mesoscopic model with the microscopic model in GFRD.
In this way the most accurate and computationally expensive method is used only where it is necessary for the accuracy
of the simulations.
A difficulty with a discretization of space by an unstructured mesh is that the computed jump probabilities by the finite element method
are negative due to poor
mesh quality. Two remedies have been devised. The first exit time also defines jump probabilities and they are always nonnegative.
By discretizing a problem with slightly different diffusion coefficients the jump probabilities are shown to be nonnegative. The
diffusion in a crowded environment is observed to behave anomalously in a transient time interval. Diffusion and reactions are modified
in the mesoscopic model by introducing internal states mimicking this behavior.
Part of the project is a collaboration
with the Elf group
at the Department of Cell and Molecular biology at Uppsala
University. Important subsystems in a cell have been analyzed mathematically and in simulations and biological conclusions have been drawn.
Financial support has been obtained from the Swedish Research Council, Swedish Foundation for Strategic Research, Göran Gustafsson Foundation, Centre for Interdisciplinary Mathematics, and the Graduate School in Mathematics and Computing. See also the homepage.
Recent papers
Z Bashardanesh, P Lötstedt, Efficient Green's Function Reaction Dynamics (GFRD) simulations for diffusion limited reversible reactions, J Comput Phys, 357 (2018), 7899. S Engblom, A Hellander, P Lötstedt, Multiscale simulation of stochastic reactiondiffusion networks, in Stochastic Processes, Multiscale Modeling, and Numerical Methods for Computational Cellular Biology, ed. D Holcman, pp 5579, Springer, Cham, 2017. A Hellander, J Klosa, P Lötstedt, S MacNamara, Robustness analysis of spatiotemporal models in the presence of extrinsic fluctuations, SIAM J Appl Math, 77 (2017), 11571183. B Drawert, A Hellander, B Bales, D Banerjee, G Bellesia, B Daigle, G Douglas, M Gu, A Gupta, S Hellander, C Horuk, G Narayanasamy, D Nath, S Wu, P Lötstedt, C Krintz, L Petzold, Stochastic Simulation Service: Bridging the gap between the computational expert and the biologist, PLoS Comput. Biol., 12 (2016), e1005220. E Blanc, S Engblom, A Hellander, P Lötstedt, Mesoscopic modeling of stochastic reactiondiffusion kinetics in the subdiffusive regime, revision in Multiscale Model. Simul., 14 (2016), 668707. L Meinecke, S Engblom, A Hellander, P Lötstedt, Analysis and design of jump coefficients in discrete stochastic diffusion models, revision in SIAM J. Sci. Comput., 38 (2016), A55A83. L Meinecke, P Lötstedt, Stochastic Diffusion Processes on Cartesian Meshes, J. Comput. Appl. Math., 294 (2016), 111. P Lötstedt, L Meinecke, Simulation of Stochastic Diffusion via First Exit Times, revised version in J. Comput. Phys., 300 (2015), 862886. S Wang, J Elf, S Hellander, P Lötstedt, Stochastic reactiondiffusion processes with embedded lower dimensional structures, revised version in Bull. Math. Biol., 76 (2014), 819853. A Grönlund, P Lötstedt, J Elf, Transcription factor binding kinetics constrain noise suppression by negative feedback, Nature Commun., 4 (2013), 1864. M H BaniHashemian, S Hellander, P Lötstedt, Efficient sampling in eventdriven algorithms for reactiondiffusion processes, revised version in Commun. Comput. Phys., 13 (2013), 958984. A Hellander, S Hellander, P Lötstedt, Coupled mesoscopic and microscopic simulation of stochastic reactiondiffusion processes in mixed dimensions, revised version in Multiscale Model. Simul., 10 (2012), 585611. A Grönlund, P Lötstedt, J Elf, Delayed induced anomalous fluctuations in intracellular regulation, Nature Commun., 2 (2011), 419. S Hellander, P Lötstedt, Flexible Single Molecule Simulation of ReactionDiffusion Processes, a revised version in J. Comput. Phys. 230 (2011), 39483965. A Grönlund, P Lötstedt, J Elf, Costs and constraints from timedelayed feedback in small gene regulatory motifs, Proc. Natl. Acad. Sci. USA, 107 (2010), 81718176 A Hellander, P Lötstedt, Incorporating Active Transport of Cellular Cargo in Stochastic Mesoscopic Models of Living Cells, revised version in Multiscale Model. Simul., 8 (2010), 16911714. L Ferm, A Hellander, P Lötstedt, An adaptive algorithm for simulation of stochastic reactiondiffusion processes, revised version in J. Comput. Phys., 229 (2010), pp. 343360. S Engblom, L Ferm, A Hellander, P Lötstedt, Simulation of stochastic reactiondiffusion processes on unstructured meshes, revised version in SIAM J. Sci. Comput. 31 (2009), 17741797. L Ferm, P Lötstedt, Adaptive solution of the master equation in low dimensions, revised version in Appl. Numer. Math. 59 (2009), 187204. P Sjöberg, P Lötstedt, J Elf, FokkerPlanck approximation of the master equation in molecular biology, revised version in Comput. Visual. Sci. 12 (2009), 3750. L Ferm, P Lötstedt, A Hellander, A hierarchy of approximations of the master equation scaled by a size parameter, revised version in J. Sci. Comput., 34 (2008), 127151. M Hegland, A Hellander, P Lötstedt, Sparse grids and hybrid methods for the chemical master equation, BIT, 48 (2008), 265284. A Hellander, P Lötstedt, Hybrid method for the chemical master equation, revised version in J. Comput. Phys., 227 (2007), 100122. L Ferm, P Lötstedt, Numerical method for coupling the macro and meso scales in stochastic chemical kinetics, revised version in BIT, 47 (2007), 735762. P Lötstedt, L Ferm, Dimensional reduction of the FokkerPlanck equation for stochastic chemical reactions, revised version in Multiscale Model. Simul. 5 (2006), 593614. L Ferm, P Lötstedt, P Sjöberg, Conservative solution of the FokkerPlanck equation in molecular biology, revised version in BIT, 46 (2006), S61S83. J Elf, P Lötstedt, P Sjöberg, Problems of high dimension in molecular biology, Proceedings of the 19th GAMMSeminar, Leipzig, January, 23th25th, 2003
PhD and licentiate theses
Stefan Engblom, Numerical Methods for the Chemical Master Equation, licentiate thesis, Uppsala University, 2006. Paul Sjöberg, Numerical Methods for Stochastic Modeling of Genes and Proteins, PhD thesis, Uppsala University, 2007. Andreas Hellander, Numerical Simulation of Well Stirred Biochemical Reaction Networks Governed by the Master Equation, licentiate thesis, Uppsala University, 2008. Stefan Engblom, Numerical Solution Methods in Stochastic Chemical Kinetics, PhD thesis, Uppsala University, 2008. Andreas Hellander, Multiscale stochastic simulation of reactiontransport processes. Applications in Molecular Systems Biology, PhD thesis, Uppsala University, 2011. Stefan Hellander, Stochastic Simulation of ReactionDiffusion Processes, PhD thesis, Uppsala University, 2013. Lina Meinecke, Stochastic Simulation of Multiscale ReactionDiffusion Models via First Exit Times, PhD thesis, Uppsala University, 2016.
Ice sheet and ice shelf modeling
Recent papers
N Kirchner, J Ahlkrona, E J Gowan, P Lötstedt, J M Lea, R Noormets, L von Sydow, J A Dowdeswell, T Benham, Shallow Ice Approximation, Second Order Shallow Ice Approximation and Full Stokes models: a discussion of their roles in palaeoice sheet modelling and development, Quat. Sci. Rev., 135 (2016), 103114. J Ahlkrona, P Lötstedt, N Kirchner, T Zwinger, Dynamically coupling the nonlinear Stokes equations with the Shallow Ice Approximation in glaciology: Description and first applications of the ISCAL method, revised version in J. Comput. Phys., 308 (2016), 119. J Ahlkrona, N Kirchner, P Lötstedt, A numerical study of scaling relations for nonNewtonian thin film flows with applications in ice sheet modeling, Quart. J. Mech. Appl. Math., 66 (2013), 417435. J Ahlkrona, N Kirchner, P Lötstedt, Accuracy of the zeroth and second order shallow ice approximation  Numerical and theoretical results, Geosci. Model Dev., 6 (2013), 21352152.
PhD thesis
Computational finance
Recent papers
E Ekström, P Lötstedt, L von Sydow, J Tysk, Numerical option pricing in the presence of bubbles, Quant. Finance, 11 (2011), 11251128. E Ekström, P Lötstedt, J Tysk, Boundary values and finite difference methods for the term structure equation, Appl. Math. Finance, 16 (2009), 253259. P Lötstedt, J Persson, L von Sydow, J Tysk, Spacetime adaptive finite difference method for European multiasset options, Comp. Math. Appl., 53 (2007), 11591180.

© Britta Lötstedt och Johanna Wedin 2006 