Multiscale Computational Modeling of Tubulin-Tubulin Lateral Interaction

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Microtubules are multistranded polymers in eukaryotic cells that support key cellular functions such as chromosome segregation, motor-based cargo transport, and maintenance of cell polarity. Microtubules self-assemble via “dynamic instability,” in which the dynamic plus ends switch stochastically between alternating phases of polymerization and depolymerization. A key question in the field is what are the atomistic origins of this switching, i.e., what is different between the GTP- and GDP-tubulin states that enables microtubule growth and shortening, respectively? More generally, a major challenge in biology is how to connect theoretical frameworks across length- and timescales, from atoms to cellular behavior. In this study, we describe a multiscale model by linking atomistic molecular dynamics (MD), molecular Brownian dynamics (BD), and cellular-level thermokinetic modeling of microtubules. Here, we investigated the underlying interaction energy when tubulin dimers associate laterally by performing all-atom MD simulations. We found that the lateral potential energy is not significantly different among three nucleotide states of tubulin, GTP, GDP, and GMPCPP and is estimated to be ≅ −11 kBT. Furthermore, using MD potential energy in our BD simulations of tubulin dimers confirms that the lateral bond is weak on its own, with a mean lifetime of ∼0.1 μs, implying that the longitudinal bond is required for microtubule assembly. We conclude that nucleotide-dependent lateral-bond strength is not the key mediator microtubule dynamic instability, implying that GTP acts elsewhere to exert its stabilizing influence on microtubule polymer. Furthermore, the estimated lateral-bond strength (ΔGlat 0≅ −5 kBT) is well-aligned with earlier estimates based on thermokinetic modeling and light microscopy measurements. Thus, we have computationally connected atomistic-level structural information, obtained by cryo-electron microscopy, to cellular-scale microtubule assembly dynamics using a combination of MD, BD, and thermokinetic models to bridge from Ångstroms to micrometers and from femtoseconds to minutes.

Original languageEnglish (US)
Pages (from-to)1234-1249
Number of pages16
JournalBiophysical journal
Volume117
Issue number7
DOIs
StatePublished - Oct 1 2019

Bibliographical note

Funding Information:
This study was supported by the National Institutes of Health under award number R01-AG053951 and the Institute for Engineering in Medicine award at the University of Minnesota to D.J.O. The authors acknowledge the Extreme Science and Engineering Discovery Environment (XSEDE) Comet at the San Diego Supercomputing Center 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 work.

Funding Information:
The authors thank Dr. Alan M. Grossfield, Dr. David Sept, Dr. Maxim Igaev, and Dr Grubm?ller for their advice and helpful discussions in preparing the manuscript. This study was supported by the National Institutes of Health under award number R01-AG053951 and the Institute for Engineering in Medicine award at the University of Minnesota to D.J.O. The authors acknowledge the Extreme Science and Engineering Discovery Environment (XSEDE) Comet at the San Diego Supercomputing Center 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 work.

Publisher Copyright:
© 2019

Fingerprint

Dive into the research topics of 'Multiscale Computational Modeling of Tubulin-Tubulin Lateral Interaction'. Together they form a unique fingerprint.

Cite this