| Title: | A novel stochastic simulation approach enables exploration of mechanisms for regulating polarity site movement |
| Author(s): | Ramirez SA; Pablo M; Burk S; Lew DJ; Elston TC; |
| Address: | "Department of Pharmacology and Computational Medicine Program, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America. Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America. Program in Molecular and Cellular Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America. Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, United States of America" |
| DOI: | 10.1371/journal.pcbi.1008525 |
| ISSN/ISBN: | 1553-7358 (Electronic) 1553-734X (Print) 1553-734X (Linking) |
| Abstract: | "Cells polarize their movement or growth toward external directional cues in many different contexts. For example, budding yeast cells grow toward potential mating partners in response to pheromone gradients. Directed growth is controlled by polarity factors that assemble into clusters at the cell membrane. The clusters assemble, disassemble, and move between different regions of the membrane before eventually forming a stable polarity site directed toward the pheromone source. Pathways that regulate clustering have been identified but the molecular mechanisms that regulate cluster mobility are not well understood. To gain insight into the contribution of chemical noise to cluster behavior we simulated clustering using the reaction-diffusion master equation (RDME) framework to account for molecular-level fluctuations. RDME simulations are a computationally efficient approximation, but their results can diverge from the underlying microscopic dynamics. We implemented novel concentration-dependent rate constants that improved the accuracy of RDME-based simulations, allowing us to efficiently investigate how cluster dynamics might be regulated. Molecular noise was effective in relocating clusters when the clusters contained low numbers of limiting polarity factors, and when Cdc42, the central polarity regulator, exhibited short dwell times at the polarity site. Cluster stabilization occurred when abundances or binding rates were altered to either lengthen dwell times or increase the number of polarity molecules in the cluster. We validated key results using full 3D particle-based simulations. Understanding the mechanisms cells use to regulate the dynamics of polarity clusters should provide insights into how cells dynamically track external directional cues" |
| Keywords: | "Algorithms Cell Membrane/physiology Cell Movement/*physiology Cell Polarity/*physiology Computational Biology *Computer Simulation Diffusion *Models, Biological Saccharomyces cerevisiae/cytology/physiology Stochastic Processes;" |
| Notes: | "MedlineRamirez, Samuel A Pablo, Michael Burk, Sean Lew, Daniel J Elston, Timothy C eng R35 GM122488/GM/NIGMS NIH HHS/ R35 GM127145/GM/NIGMS NIH HHS/ Research Support, N.I.H., Extramural 2021/07/16 PLoS Comput Biol. 2021 Jul 15; 17(7):e1008525. doi: 10.1371/journal.pcbi.1008525. eCollection 2021 Jul" |
