Atomistic basis of microtubule dynamic instability assessed via multiscale modeling

Abstract

Microtubule "dynamic instability," the abrupt switching from assembly to disassembly caused by the hydrolysis of GTP to GDP within the β subunit of the αβ-tubulin heterodimer, is necessary for vital cellular processes such as mitosis and migration. Despite existing high-resolution structural data, the key mechanochemical differences between the GTP and GDP states that mediate dynamic instability behavior remain unclear. Starting with a published atomic-level structure as an input, we used multiscale modeling to find that GTP hydrolysis results in both longitudinal bond weakening (~4 kBT) and an outward bending preference (~1.5 kBT) to both drive dynamic instability and give rise to the microtubule tip structures previously observed by light and electron microscopy. More generally, our study provides an example where atomic level structural information is used as the sole input to predict cellular level dynamics without parameter adjustment.

Equilibrium mechanisms of self-limiting assembly

“…These nonequilibrium processes not only allow stable finite-length distributions, but also structural dynamics, such as actin treadmilling and microtubule dynamical instability, that allow the cellular cytoskeleton to rapidly respond and reconfigure to environmental cues. Using models ranging from idealized onedimensional filaments to geometrically realistic particlebased dynamical simulations (Bollinger and Stevens, 2018;Fai et al, 2019;Hemmat and Odde, 2020;Mohapatra et al, 2016;Tong and Voth, 2020), researchers have identified multiple mechanisms by which active filament assembly/disassembly processes and energy-driven subunit conformational changes can lead to 1D filaments which exhibit dynamical instabilities and/or with welldefined stable sizes. In contrast, recall from section II.A.2 that equilibrium 1D filaments generically exhibit exponential length distributions.…”