Microscopic simulations show allosteric compaction in microtubules drives catastrophe
Jonathan A. Bollinger and Mark J. Stevens
Center for Integrated Nanotechnologies, Sandia National Laboratories, Albuquerque NM 87185
Microtubules (MTs) are rigid biopolymers critical for many cellular processes including mitosis, and consist of αβ-tubulin dimers arranged in filaments to form hollow cylinders up to microns in length. MTs possess an unusual polymerization instability. Growth proceeds as dimers with GTP bound to their β-subunits (i.e., GTP-tubulin) slowly assemble onto the end of the MT, while dimers in the MT lattice away from the GTP-tubulin “cap” are converted to GDP-tubulin via dephosphorylation. Once the cap disappears, a catastrophically fast depolymerization occurs in which the MT filaments (populated with GDP-tubulin) unpeel via a well-known “rams’ horns” motif. Understanding this depolymerization is fundamental to MTs, but a full calculation of the dynamics has not been possible. One hypothesis is that the switch from a GTP- to GDP-tubulin causes allosteric compaction in the α-subunit of the neighboring dimer, which generates mechanical stress in the tubule sufficient to drive catastrophe once the stabilizing GTP cap disappears.
To investigate whether compaction in GDP-proximal tubulin can drive catastrophic unpeeling, we perform molecular simulations of MTs assembled from coarse-grained αβ-tubulin dimers, based on a previously developed model that treated tubule self-assembly. We mimic the dephosphorylation-driven allostery by angling the bottom surfaces of α-subunits in the tubule lattice. Our simulations show that this shape transformation does indeed induce MTs to catastrophically depolymerize via the well-known “rams’ horns” pathway. Notably, we observe catastrophic events only around compaction angles resembling the “bent” dimer conformation experimentally measured in bulk solution, and at subunit attraction strengths consistent with recent experimental estimates. Furthermore, we show that compacted MTs can be stabilized via very short non-compacted (i.e., GTP-tubulin) end caps. Thus, we demonstrate that mechanical stress due to the shape change between GTP- and GDP-associated tubulin can cause catastrophic depolymerization.