CellDynaMo-stochastic reaction-diffusion-dynamics model: Application to search-and-capture process of mitotic spindle assembly

We introduce a Stochastic Reaction-Diffusion-Dynamics Model (SRDDM) for simulations of cellular mechanochemical processes with high spatial and temporal resolution. The SRDDM is mapped into the CellDynaMo package, which couples the spatially inhomogeneous reaction-diffusion master equation to account for biochemical reactions and molecular transport within the Langevin Dynamics (LD) framework to describe dynamic mechanical processes. This computational infrastructure allows the simulation of hours of molecular machine dynamics in reasonable wall-clock time. We apply SRDDM to test performance of the Search-and-Capture of mitotic spindle assembly by simulating, in three spatial dimensions, dynamic instability of elastic microtubules anchored in two centrosomes, movement and deformations of geometrically realistic centromeres with flexible kinetochores and chromosome arms. Furthermore, the SRDDM describes the mechanics and kinetics of Ndc80 linkers mediating transient attachments of microtubules to the chromosomal kinetochores. The rates of these attachments and detachments depend upon phosphorylation states of the Ndc80 linkers, which are regulated in the model by explicitly accounting for the reactions of Aurora A and B kinase enzymes undergoing restricted diffusion. We find that there is an optimal rate of microtubule-kinetochore detachments which maximizes the accuracy of the chromosome connections, that adding chromosome arms to kinetochores improve the accuracy by slowing down chromosome movements, that Aurora A and kinetochore deformations have a small positive effect on the attachment accuracy, and that thermal fluctuations of the microtubules increase the rates of kinetochore capture and also improve the accuracy of spindle assembly. Author summary The CellDynaMo package models, in 3D, any cellular subsystem where sufficient detail of the macromolecular players and the kinetics of relevant reactions are available. The package is based on the Stochastic Reaction-Diffusion-Dynamics model that combines the stochastic description of chemical kinetics, Brownian diffusion-based description of molecular transport, and Langevin dynamics-based representation of mechanical processes most pertinent to the system. We apply the model to test the Search-and-Capture mechanism of mitotic spindle assembly. We find that there is an optimal rate of microtubule-kinetochore detachments which maximizes the accuracy of chromosome connections, that chromosome arms improve the attachment accuracy by slowing down chromosome movements, that Aurora A kinase and kinetochore deformations have small positive effects on the accuracy, and that thermal fluctuations of the microtubules increase the rates of kinetochore capture and also improve the accuracy.