Twist-Bending Elasticity And Energetics Of The Plus-End Microtubule Tip Captured By Exascale Atomistic Simulations

Tubulin dimers associate longitudinally and laterally to form microtubules (MTs) that stochastically alternate between phases of growth and shrinkage. Assembly is favored upon GTP binding, whereas GTP hydrolysis within the MT encourages disassembly. Recent experiments with high-resolution cryoelectron microscopy, complemented by our molecular dynamics (MD) simulations of both free and MT-integrated tubulin [Igaev, M. and H. Grubmüller. eLife 2018;7:e34353, Igaev, M. and H. Grubmüller. PLoS Comp. Biol. 2020;16(9):e1008132], suggested that most of the hydrolysis energy is spent to increase mechanical strain along the MT lattice and to decrease intra-lattice correlations. It is therefore conceivable that, during disassembly, MTs would release the excess tension, which lateral bonds can no longer counteract. However, due to the system complexity and the inability of modern structural methods to visualize the disassembly process, the physical principles behind MT instability remain elusive. Here we used exascale molecular dynamics (MD) simulations to study the spatiotemporal distribution of the MT plus-end elasticity at the atomistic level. Starting from a blunt-end MT structure, our fluctuation and force distribution analyses revealed a strong dependence of the relaxation to a ‘flared’ MT on the nucleotide state. Further, we observed an unexpected heterogeneity in protofilament splaying along the MT circumference, except at the seam, which was prone to splaying in all of our simulations. However, the magnitude of crack opening at the seam was not significantly larger than elsewhere, arguing against its mechanical weakness. Finally, we found that the plus-end relaxation arises from two distinct contributions, the bending elasticity of protofilaments and the torsional elasticity about the protofilaments’ centerline. Separation of these contributions provides a minimal quantitative model of the plus-end energetics along the bending-torsional degrees of freedom and offers new insights into the mechanodynamics of MT instability.