Microtubule instability driven by longitudinal and lateral strain propagation

Tubulin dimers associate longitudinally and laterally to form metastable microtubules (MTs). MT disassembly is preceded by subtle structural changes in tubulin fueled by GTP hydrolysis. These changes render the MT lattice unstable, but it is unclear exactly how they affect lattice energetics and strain. We performed long-time atomistic simulations to interrogate the impacts of GTP hydrolysis on tubulin lattice conformation, lateral inter-dimer interactions, and (non-)local lateral coordination of dimer motions. The simulations suggest that most of the hydrolysis energy is stored in the lattice in the form of longitudinal strain. While not significantly affecting lateral bond stability, the stored elastic energy results in more strongly confined and correlated dynamics of GDP-tubulins, thereby entropically destabilizing the MT lattice.Author summary: The dynamic nature of microtubules, long and hollow tubes formed by αβ-tubulin proteins, is crucial for their function is cells, and its precise characterization has been a long-standing problem for cell scientists. Microtubules are essential for cargo transport and provide mechanical forces in chromosome segregation when they disassemble. The disassembly proceeds via changes in the shapes of tubulins upon consumption of a chemical fuel called GTP that binds to every tubulin molecule. This leads to the accumulation of mechanical tension inside the microtubule and ultimately drives it beyond the stability threshold. However, it is still elusive how and where these shape changes contribute to the rapid release of the stored elastic energy. Here, we investigate the behavior of tubulin dimers in a microtubule-like environment using extensive atomistic simulations and show that tubulins locked in the microtubule operate as both ‘loadable springs’ and ‘conformational switches’, tightly controlled by their surrounding neighbours. We further show how these shape changes potentially control the overall stability of the microtubule, providing quantitative estimates of the system’s energetics.