Onset and Arrest of Catastrophic Depolymerization in Microtubules Controlled by Tubulin Subunit Shape

Microtubules are biopolymers critical for cellular function that display rich dynamic and mechanical behaviors. While microtubules are one of the stiffest known polymers, they possess a distinct dynamic instability: tubules self-assemble via the addition of GTP-tubulin dimers (tubulin bound to GTP), but hydrolysis of GTP- to GDP-tubulin within the tubules eventually destabilizes them toward catastrophically-fast depolymerization, if the leading cap of GTP-tubulin is lost. The molecular mechanisms and features of the individual tubulin proteins that drive such apparently contradictory behavior are still not well-understood. Using molecular dynamics simulations of whole microtubules built from a new coarse-grained model of tubulin, we demonstrate that conformational changes in subunits that frustrate tubulin binding, which have long been hypothesized as a part of microtubule dynamics, drive depolymerization via the unpeeling ``ram's horns'' consistent with experiments. We also show how depolymerization can be prevented or even arrested in-progress (the latter allowing rescue and regrowth) by the presence of even very few GTP-tubulin dimers, and explore the ranges of binding interaction strengths and degrees of shape frustration for which these behaviors are possible.