Computational modeling of cellular signaling processes embedded into dynamic spatial contexts

Abstract

Cellular signaling processes depend on specific spatiotemporal distributions of their molecular components. Multi-color high-resolution microscopy now permits detailed assessment of such distributions, providing the input for fine-grained computational models that explore the mechanisms governing dynamic assembly of multi-molecular complexes and their role in shaping cellular behavior. However, incorporating into such models both complex molecular reaction cascades and the spatial localization of signaling components within dynamic cellular morphologies presents substantial challenges. Here we introduce an approach that addresses these challenges by automatically generating computational representations of complex reaction networks based on simple bi-molecular interaction rules embedded into detailed, adaptive models of cellular morphology. Using examples of receptor-mediated cellular adhesion and signal-induced localized MAPK activation in yeast, we illustrate the capacity of this simulation technique to provide insights into cell biological processes. The modeling algorithms, implemented in a version of the Simmune tool set, are accessible through intuitive graphical interfaces as well as programming libraries.

Network as biomarker

“…The integrative effort of piecing basic findings together has perhaps not been given proper attention. Such integrative effort, from a computational point of view, can be seen in work such as, [76][77][78] in which the objective is to collect basic information and integrate it into a whole biological process. This integrative computational biology is the bridge between the reduction we see in screening thousands of patients into their core genes or core molecular pathways, and the intensity with which these basic findings are brought to the clinic.…”

An Analysis of the Truncated Bid- and ROS-dependent Spatial Propagation of Mitochondrial Permeabilization Waves during Apoptosis

“…In the future, more advanced spatiotemporal modeling approaches may therefore be required to investigate the impact of cell shapes and also the impact of other features, such as intracellular diffusion barriers (for example, other organelles and their membrane barriers that need to be circumvented). Approaches by which the intracellular space is discretized into voxels and that employ rules-based logic modeling appear to be attractive strategies to achieve this (32,33). Such modeling approaches may also be suited to take into account complex changes in mitochondrial connectivity and trafficking that go beyond the simple scenarios of mitochondrial discontinuities analyzed in our study.…”

Multiscale Modeling of the Early CD8 T-Cell Immune Response in Lymph Nodes: An Integrative Study

“…In our study, we used the CompuCell3D open-source simulation environment. Other immune-based frameworks exist (e.g., C-ImmSim [51], Simmune [52]) and could well be applied. It would be very interesting in the future to compare model results emerging from different model frameworks.…”