Atomistic Basis of Microtubule Dynamic Instability Assessed Via Multiscale Modeling

Microtubule dynamic instability, the abrupt switching from assembly to disassembly caused by the hydrolysis of GTP to GDP within the beta subunit of the alpha beta-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 (similar to 4 k(B)T) and an outward bending preference (similar to 1.5 k(B)T) 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.

Automated summary

This study uses multiscale modeling to show that GTP hydrolysis results in both longitudinal bond weakening and an outward bending preference, which together drive microtubule dynamic instability and lead to the observed microtubule tip structures. This research demonstrates the use of atomic-level structural information as the sole input to predict cellular-level dynamics without parameter adjustment.