Atomistic Basis of Microtubule Dynamic Instability Assessed Via Multiscale Modeling

Mahya Hemmat; David J. Odde

doi:10.1007/s10439-020-02715-6

Atomistic Basis of Microtubule Dynamic Instability Assessed Via Multiscale Modeling

Mahya Hemmat, David J. Odde

Biomedical Engineering

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

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 k_BT) and an outward bending preference (~ 1.5 k_BT) 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.

Original language	English (US)
Pages (from-to)	1716-1734
Number of pages	19
Journal	Annals of Biomedical Engineering
Volume	49
Issue number	7
Early online date	Feb 3 2021
DOIs	https://doi.org/10.1007/s10439-020-02715-6
State	Published - Jul 2021

Bibliographical note

Funding Information:
The authors thank Dr. Jonathan Sachs for advice and helpful discussions. This study was supported by National Institutes of Health under Award Number RF1-AG053951 and the Institute for Engineering in Medicine (IEM) award at the University of Minnesota to DJO. The authors acknowledge the Extreme Science and Engineering Discovery Environment (XSEDE), Comet system at the San Diego Supercomputing Center (SDSC) and Bridges system at the Pittsburgh Supercomputing Center (PSC) through allocation MCB160060, and the Minnesota Supercomputing Institute (MSI) at the University of Minnesota for providing resources that contributed to the research results reported within this paper.

Funding Information:
The authors thank Dr. Jonathan Sachs for advice and helpful discussions. This study was supported by National Institutes of Health under Award Number RF1-AG053951 and the Institute for Engineering in Medicine (IEM) award at the University of Minnesota to DJO. The authors acknowledge the Extreme Science and Engineering Discovery Environment (XSEDE), Comet system at the San Diego Supercomputing Center (SDSC) and Bridges system at the Pittsburgh Supercomputing Center (PSC) through allocation MCB160060, and the Minnesota Supercomputing Institute (MSI) at the University of Minnesota for providing resources that contributed to the research results reported within this paper. This work is based on the preprint submission on bioRxiv.org: ?Atomistic basis of microtubule dynamic instability assessed via multiscale modeling?, https://doi.org/10.1101/2020.01.07.897439 Copyright holder for this preprint is the author/funder and it is made available under a CC-BY-NC-ND 4.0 International license. Conceptualization: MH and DJO; Methodology: MH, and DJO; Software: MH; Analysis: MH, and DJO; Writing, Original Draft: MH and DJO; Writing, Review & Editing, all authors; Visualization: MH; Supervision: DJO; and Funding Acquisition: DJO.

Publisher Copyright:
© 2021, The Author(s).

Keywords

Brownian dynamics
Molecular dynamics
Thermokinetic modeling
Tubulin

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10.1007/s10439-020-02715-6

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title = "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.",

keywords = "Brownian dynamics, Molecular dynamics, Thermokinetic modeling, Tubulin",

author = "Mahya Hemmat and Odde, {David J.}",

note = "Funding Information: The authors thank Dr. Jonathan Sachs for advice and helpful discussions. This study was supported by National Institutes of Health under Award Number RF1-AG053951 and the Institute for Engineering in Medicine (IEM) award at the University of Minnesota to DJO. The authors acknowledge the Extreme Science and Engineering Discovery Environment (XSEDE), Comet system at the San Diego Supercomputing Center (SDSC) and Bridges system at the Pittsburgh Supercomputing Center (PSC) through allocation MCB160060, and the Minnesota Supercomputing Institute (MSI) at the University of Minnesota for providing resources that contributed to the research results reported within this paper. Funding Information: The authors thank Dr. Jonathan Sachs for advice and helpful discussions. This study was supported by National Institutes of Health under Award Number RF1-AG053951 and the Institute for Engineering in Medicine (IEM) award at the University of Minnesota to DJO. The authors acknowledge the Extreme Science and Engineering Discovery Environment (XSEDE), Comet system at the San Diego Supercomputing Center (SDSC) and Bridges system at the Pittsburgh Supercomputing Center (PSC) through allocation MCB160060, and the Minnesota Supercomputing Institute (MSI) at the University of Minnesota for providing resources that contributed to the research results reported within this paper. This work is based on the preprint submission on bioRxiv.org: ?Atomistic basis of microtubule dynamic instability assessed via multiscale modeling?, https://doi.org/10.1101/2020.01.07.897439 Copyright holder for this preprint is the author/funder and it is made available under a CC-BY-NC-ND 4.0 International license. Conceptualization: MH and DJO; Methodology: MH, and DJO; Software: MH; Analysis: MH, and DJO; Writing, Original Draft: MH and DJO; Writing, Review & Editing, all authors; Visualization: MH; Supervision: DJO; and Funding Acquisition: DJO. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

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AU - Odde, David J.

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N2 - 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.

AB - 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.

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KW - Molecular dynamics

KW - Thermokinetic modeling

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ER -

Atomistic Basis of Microtubule Dynamic Instability Assessed Via Multiscale Modeling

Abstract

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