Microtubule catastrophe under force: mathematical and computational results from a Brownian ratchet model.

In the intracellular environment, the intrinsic dynamics of microtubule filaments is often hindered by the presence of barriers of various kind, such as kinetochore complexes and cell cortex, which impact their polymerisation force and dynamical properties such as catastrophe frequency. We present a theoretical study of the effect of a forced barrier, also subjected to thermal noise, on the statistics of catastrophe events in a single microtubule as well as a 'bundle' of two parallel microtubules. For microtubule dynamics, which includes growth, detachment, hydrolysis and the consequent dynamic instability, we employ a one-dimensional discrete stochastic model. The dynamics of the barrier is captured by over-damped Langevin equation, while its interaction with a growing filament is assumed to be hard-core repulsion. A unified treatment of the continuum dynamics of the barrier and the discrete dynamics of the filament is realized using a hybrid Fokker-Planck equation. An explicit mathematical formula for the force-dependent catastrophe frequency of a single microtubule is obtained by solving the above equation, under some assumptions. The prediction agrees well with results of numerical simulations in the appropriate parameter regime. More general situations are studied via numerical simulations. To investigate the extent of 'load-sharing' in a microtubule bundle, and its impact on the frequency of catastrophes, the dynamics of a two-filament bundle is also studied. Here, two parallel, non-interacting microtubules interact with a common, forced barrier. The equations for the two-filament model, when solved using a mean-field assumption, predicts equal sharing of load between the filaments. However, numerical results indicate the existence of a wide spectrum of load-sharing behaviour, which is characterized using a dimensionless parameter.