Microtubule Simulations Provide Insight into the Molecular Mechanism Underlying Dynamic Instability

Abstract

The dynamic instability of microtubules (MTs), which refers to their ability to switch between polymerization and depolymerization states, is crucial for their function. It has been proposed that the growing MT ends are protected by a ''GTP cap'' that consists of GTP-bound tubulin dimers. When the speed of GTP hydrolysis is faster than dimer recruitment, the loss of this GTP cap will lead the MT to undergo rapid disassembly. However, the underlying atomistic mechanistic details of the dynamic instability remains unclear. In this study, we have performed long-time atomistic molecular dynamics simulations (1 ms for each system) for MT patches as well as a short segment of a closed MT in both GTP-and GDP-bound states. Our results confirmed that MTs in the GDP state generally have weaker lateral interactions between neighboring protofilaments (PFs) and less cooperative outward bending conformational change, where the difference between bending angles of neighboring PFs tends to be larger compared with GTP ones. As a result, when the GDP state tubulin dimer is exposed at the growing MT end, these factors will be more likely to cause the MT to undergo rapid disassembly. We also compared simulation results between the special MT seam region and the remaining material and found that the lateral interactions between MT PFs at the seam region were comparatively much weaker. This finding is consistent with the experimental suggestion that the seam region tends to separate during the disassembly process of an MT.

Atomistic Basis of Microtubule Dynamic Instability Assessed Via Multiscale Modeling

“…S5), and found that a COM reaction coordinate can best mesh together the MD to BD scales. Additionally, it will be important in the future for our thermokinetic model to include minus end dynamics as another way to validate our modeling results as well as long-range effect of neighbors 38 (without ad hoc parametrization) and the seam interactions 64 to investigate their potential effects on the interaction energies.…”

Microtubule instability driven by longitudinal and lateral strain propagation

“…In contrast, the holistic or bond model [23,27] assumes that MT catastrophe can be explained by a sequential weakening of lateral inter-dimer contacts accompanied by a simultaneous strengthening of longitudinal contacts. Also here, recent atomistic simulations of full MT lattices suggest that lateral interactions in GDP-MTs might be weaker than those in GTP-MTs [25]. Finally, the most recent 'no expansion' model [24] provides an alternative view of the cap maturation process in which both pure GTP-and pure GDP-MTs have equally compacted lattices, while the higher-energy expanded lattice induced by GTP hydrolysis (mimicked by GMPCPP) corresponds to an intermediate, phosphate-releasing state.…”

“…In this model, lattice rupture is initiated at the seam because of the greater distance, and presumably weaker interactions, between PFs at this interface observed in unsymmetrized cryo-EM reconstructions. The role of the MT seam as the weakest interface is supported by recent computational evidence [25], but has been challenged experimentally [26]. In contrast, the holistic or bond model [23,27] assumes that MT catastrophe can be explained by a sequential weakening of lateral inter-dimer contacts accompanied by a simultaneous strengthening of longitudinal contacts.…”

Coarse-Grained Simulation of Mechanical Properties of Single Microtubules With Micrometer Length

“…Theoretical modeling of microtubules ( Kasas et al, 2004a ; Kasas et al, 2004b ; Molodtsov et al, 2005 ; VanBuren et al, 2005 ; Schaap et al, 2006 ; Deriu et al, 2007 ; Heuvel et al, 2007 ; Deriu et al, 2008 ; Dima and Joshi, 2008 ; Deriu et al, 2010 ; Sept and MacKintosh, 2010 ; Wells and Aksimentiev, 2010 ; Grafmuller and Voth, 2011 ; Ji and Feng, 2011a ; b ; Peter and Mofrad, 2012 ; Grafmuller et al, 2013 ; Theisen et al, 2013 ; Kononova et al, 2014 ; Lazarus et al, 2015 ; Soheilypour et al, 2015 ; Havelka et al, 2017 ; Stevens, 2017 ; Szatkowski et al, 2019 ; Tong and Voth, 2020 ) faces a huge challenge due to the micrometer length. All-atom molecular dynamics (MD) simulations have been primarily used to investigate the atomistic details of the interactions between the α- and β-tubulins ( Deriu et al, 2007 ; Deriu et al, 2008 ; Sept and MacKintosh, 2010 ; Wells and Aksimentiev, 2010 ; Grafmuller and Voth, 2011 ; Grafmuller et al, 2013 ; Havelka et al, 2017 ) for short microtubules.…”

“…All-atom molecular dynamics (MD) simulations have been primarily used to investigate the atomistic details of the interactions between the α- and β-tubulins ( Deriu et al, 2007 ; Deriu et al, 2008 ; Sept and MacKintosh, 2010 ; Wells and Aksimentiev, 2010 ; Grafmuller and Voth, 2011 ; Grafmuller et al, 2013 ; Havelka et al, 2017 ) for short microtubules. Recent all-atom simulations ( Tong and Voth, 2020 ) reached a length scale of a 1 μm microtubule including 3 protofilaments. Additionally, coarse-grained (CG) models ( Dima and Joshi, 2008 ; Deriu et al, 2010 ; Ji and Feng, 2011a ; Ji and Feng, 2011b ; Theisen et al, 2013 ; Kononova et al, 2014 ; Lazarus et al, 2015 ; Soheilypour et al, 2015 ; Stevens, 2017 ; Szatkowski et al, 2019 ) have also been used to model longer microtubules.…”