Microtubule assembly governed by tubulin allosteric gain in flexibility and lattice induced fit

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Abstract

Microtubules (MTs) are key components of the cytoskeleton and play a central role in cell division and development. MT assembly is known to be associated with a structural change in αβ-tubulin dimers from kinked to straight conformations. How GTP binding renders individual dimers polymerization-competent, however, is still unclear. Here, we have characterized the conformational dynamics and energetics of unassembled tubulin using atomistic molecular dynamics and free energy calculations. Contradictory to existing allosteric and lattice models, we find that GTP-tubulin favors a broad range of almost isoenergetic curvatures, whereas GDP-tubulin has a much lower bending flexibility. Moreover, irrespective of the bound nucleotide and curvature, two conformational states exist differing in location of the anchor point connecting the monomers that affects tubulin bending, with one state being strongly favored in solution. Our findings suggest a new combined model in which MTs incorporate and stabilize flexible GTP-dimers with a specific anchor point state.

Data availability

A step-by-step guide for reproducing the simulations and all custom-made scripts used in this study have been uploaded to a publicly available GitHub repository (https://github.com/moozzz/simulation-protocols/tree/master/free-tubulin-simulation).

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Maxim Igaev

Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany

For correspondence
migaev@mpibpc.mpg.de

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-8781-1604
Helmut Grubmüller

Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany

For correspondence
hgrubmu@gwdg.de

Competing interests
The authors declare that no competing interests exist.

Funding

Max Planck Society (Open-access funding)

Maxim Igaev
Helmut Grubmüller

Deutsche Forschungsgemeinschaft (IG 109/1-1)

Maxim Igaev

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.