BPS2026 – Multiscale modeling for microtubule dynamics: From bending relaxation to hydrolysis kinetics

Microtubules are essential cytoskeleton components that play an important role in cellular architecture, intracellular transport, and chromosome segregation. The dynamic instability of their plus-end enables these functions, while the underlying relationship to nucleotide hydrolysis is less clear. Recent all-atom simulations and cryo-ET structures have revealed stable protofilament clusters at the plus-end in both nucleotide states. With extensive all-atom simulation and analysis, we revealed a mechanism for the formation of such protofilament clusters, driven first by longitudinal relaxation and outward bending and later stabilized by lateral interaction. We also constructed a bottom-up coarse-grained model with a 20-per-site resolution to extrapolate the bending dynamics to longer timescales and larger microtubule systems. The protofilament clusters remain stable up to tens of microseconds of CG MD simulation time, and their formation in turn stabilizes the microtubule lattice via lattice curvature and in-lattice twisting. Weakened lateral interactions in GDP-bound tubulins favor more protofilament clusters and more outward bending. We have also developed a non-equilibrium ultra-coarse-graining model based on kinetic Monte Carlo to incorporate GTP-tubulin binding and hydrolysis events in the microtubule model, in order to investigate possible cooperative effects between hydrolysis, bending relaxation, and microtubule catastrophe.