Bottom-up coarse-grained model of microtubule dynamics: A bridge between length- and timescales

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Microtubules, one of the principal components of the cytoskeleton, play critical roles in cell division, maintenance of cell shape and intracellular transport. A key feature of microtubule (MT) function is dynamic instability, the stochastic switching between periods of shortening (catastrophe) and growth (rescue). A growing body of evidence connects dynamic instability to the hydrolysis of GTP by β-tubulin monomers, but their exact coupling is hard to assess due to the orders of magnitude separation in length- and timescales. In order to bridge the scales of GTP hydrolysis and MT dynamics, we parametrized a monomer-resolution coarse-grained (CG) model based on ∼4 μs all-atom molecular dynamics (MD) simulations of the MT tip. Effective CG potentials for local two- (bonds), three- (angles), and four-body (dihedral) interactions were determined using a modified form of the Iterative Boltzmann Inversion method, which accounts for explicit bond breaking between neighboring protofilaments. Application of Brownian dynamics to our MT CG model allowed for simulations on timescales inaccessible by current all-atom MD simulations, while also bridging GTP hydrolysis with MT dynamics. We used the MT CG model to evaluate MT dynamics in different conditions of GTP and GDP.