Skora, T.; Wu, J.; Beckett, D.; Xue, W.; Voth, G. A.; Bidone, T. C.

Microtubules are essential cytoskeletal components with a broad range of functions in which the structure and dynamics of their plus-end tips play critical roles. Existing mechanistic models explain the tips curving dynamics in different ways: the allosteric model suggests that GTP hydrolysis induces conformational changes in tubulin subunits that destabilize the lattice, leading to protofilament curving and depolymerization, while the lattice model posits that GTP hydrolysis directly destabilizes the microtubule lattice. However, the effect of GTP hydrolysis on the curving dynamics of microtubule tips remains incompletely understood. In this study, we employed a multiscale modeling approach, combining all-atom molecular dynamics simulations with Brownian dynamics simulations, to investigate the relaxation of microtubule plus-end tips into curved configurations. Our results show that both GDP- and GTP-bound tips exhibit an outward bending of protofilaments into curved, rams horn-like structures, characterized by a linear relationship between curvature and distance from the plus-end tip. These observations align with experimental cryo-ET images of microtubule plus-end tips in different nucleotide states. Collectively, our findings suggest that the outward bending of protofilaments at the plus-end tip is an intrinsic feature of microtubules, independent of the nucleotide state.