Agent-Based Modeling in Molecular Systems Biology

mRNA is packaged into ribonucleoprotein particles called mRNPs. A multitude of RNA-binding proteins as well as a host of associated proteins participate in the fate of mRNA from transcription and processing in the nucleus to translation and decay in the cytoplasm. Methodological innovations in cell biology and genome-wide high-throughput approaches have revealed an unexpected diversity of mRNA-associated proteins and unforeseen interconnections between mRNA-processing steps. Recent insights into mRNP formation in vivo have also highlighted the importance of mRNP packaging, which can sort RNAs on the basis of their length and determine mRNA fate through alternative mRNP assembly, processing and export pathways.

Recent advances focusing on the metabolic interactions within and between cellular populations have emphasized the importance of microbial communities for human health. Constraint-based modeling, with flux balance analysis in particular, has been established as a key approach for studying microbial metabolism, whereas individual-based modeling has been commonly used to study complex dynamics between interacting organisms. In this study, we combine both techniques into the R package BacArena (https://cran.r-project.org/package=BacArena) to generate novel biological insights into Pseudomonas aeruginosa biofilm formation as well as a seven species model community of the human gut. For our P. aeruginosa model, we found that cross-feeding of fermentation products cause a spatial differentiation of emerging metabolic phenotypes in the biofilm over time. In the human gut model community, we found that spatial gradients of mucus glycans are important for niche formations which shape the overall community structure. Additionally, we could provide novel hypothesis concerning the metabolic interactions between the microbes. These results demonstrate the importance of spatial and temporal multi-scale modeling approaches such as BacArena.

Export of mRNA occurs via nuclear pores, large nano-machines with diameters of roughly 120 nm that are the only link between nucleus and cytoplasm1. Hence, mRNA export occurs over distances smaller than the optical resolution of conventional light microscopes. There is extensive knowledge on the physical structure and composition of the NPC2–7, but transport selectivity and dynamics of mRNA export at nuclear pores remain unknown8. We developed a super-registration approach using fluorescence microscopy that can overcome the current limitations of colocalization by means of measuring intermolecular distances of chromatically different fluorescent molecules with nm precision. With this method we achieve 20 ms time- and at least26 nm spatial precision, rendering the capture of highly transient interactions in living cells possible. With this method we were able to spatially resolve the kinetics of mRNA transport and present a three step model consisting of docking (80ms), transport (5–20ms) and release (80ms), totalling 180 ± 10 ms. Importantly, the translocation through the channel was not the rate-limiting step, mRNAs can move bi-directionally in the pore complex and not all pores are equally active.