Catastrophic Depolymerization of Microtubules Driven by Tubulin Subunit Shape Change

Microtubules exhibit a distinctive dynamic instability between growth and catastrophically-fast depolymerization. GTP-tubulin (a dimer bound to GTP) self-assembles, but dephosphorylation of GTP- to GDP-tubulin within the tubule results in destabilization. The molecular origins of this instability have remained unclear despite their importance for bioengineering strategies. One hypothesis is that dephosphorylation causes tubulin to change shape, frustrating bonds and generating stress. To test this idea, we perform molecular dynamics simulations of microtubules built from a new coarse-grained model of tubulin, implementing conformational changes in tubulin thought to drive the instability. We find that this shape change induces depolymerization via unpeeling ''ram's horns'' characteristic of microtubules. Depolymerization can be averted by caps with undeformed dimers, i.e., GTP-rich regions, and model microtubules exhibit mechanical responses consistent with experiments.