Microtubule instability driven by longitudinal and lateral strain propagation

Abstract

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.

Bending-torsional elasticity and energetics of the plus-end microtubule tip

“…2C ). This finding correlates well with a recent MD study showing that GTP hydrolysis results in a ∼4 k B T longitudinal bond weakening [36] as well as with our previous finding that the longitudinal bonds in GDP-PFs are more fragile when subject to mechanical stretching [35]. We note, however, that the FDA provides only the enthalpic contribution to the longitudinal stability because the entropic penalty for eliminating solvent from tubulin's surface is not taken into account.…”

“…Relaxation dynamics and heterogeneity of MT plus-end tips At the MT tip, the elastic energy stored by straightened PFs is only insufficiently balanced by the total energy of lateral dimer-dimer interactions, which results in MT structures featuring irregularly splayed, curved PFs [25,26,27]. Recent atomistic MD simulation have predicted substantial differences in the bending rigidity of GTP-and GDP-bound free dimers, single PFs, and tubulin octamers [31,32,33,34,35,36]. Concomitantly, it has been proposed that the formation/breakage of lateral dimer-dimer contacts might also be nucleotide-dependent [37,38,39].…”

“…To this end, we constructed two initial atomistic models of GTP-and GDP-MT tips by consecutively stacking three identical MT segments, each comprising two layers of dimers and each optimized against the high-resolution cryo-EM densities of GMPCPP-or GDP-MTs [40,41,35] (see Fig. 1B and Methods for a detailed simulation protocol).…”

Depolymerization of supramolecular polymers by a covalent reaction; transforming an intercalator into a sequestrator

“…A fascinating example on how nature controls dynamic supramolecular systems by incorporating covalent reactions is the dynamic instability of microtubules that governs their cyclic growth and shrinkage. 4,5 Microtubules consist of a/b-tubulin molecules that can polymerize into long bres by incorporation of guanosine di-or triphosphate (GDP or GTP) on the growing end of the tubules. Hydrolysis of GTP into GDP destabilizes the bre and triggers depolymerization.…”

“…Addition of new GTP to the stack stabilizes the bre and initiates the growth cycle again. 4,5 Integration of this ne level of control and precision over aggregation mechanisms by combining covalent and noncovalent synthesis would be of great interest to tackle the challenge of recyclability of supramolecular materials. Inspired by these systems, the interplay between structure and reactivity can serve as a stepping stone towards the design of functional and life-like 1D supramolecular materials.…”