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Albany 2015:Book of Abstracts

Albany 2015
Conversation 19
June 9-13 2015
©Adenine Press (2012)

Tubulin bond energies and microtubule biomechanics determined from nanoindentation in silico

Microtubules (MTs) play essential roles in health and viability of eukaryotic cells. MTs are stabilized by longitudinal and lateral non-covalent bonds between the αβ -tubulin subunits. However, the thermodynamics of these bonds and the MT physico-chemical properties are poorly understood. In this study, we explore the biomechanics of MT polymers using multiscale computational modeling and nanoindentations in silico of a contiguous MT fragment. Our approach is based on a combination of the Self-Organized Polymer model and all-atom Molecular Dynamic simulations of the MT fragment, accelerated on Graphic Processing Units (Zhmurov et al. 2010). Good agreement between the simulated and experimental force-deformation spectra (de Pablo et al. 2003) enabled us to correlate the MT biomechanics with dynamic structural transitions at the nanoscale. Our mechanical testing revealed that the compressed MT behaves as a system of rigid elements interconnected through a network of lateral and longitudinal elastic bonds. The initial regime of continuous elastic deformation of the MT is followed by discrete structural transitions, which include first the reversible dissociation of lateral bonds and then irreversible dissociation of the longitudinal bonds. From our simulations we have determined the free energies of dissociation of the lateral (6.9±0.4 kcal/mol) and longitudinal (14.9±1.5 kcal/mol) tubulin-tubulin bonds. These values, in conjunction with the large flexural rigidity of tubulin protofilaments we obtained (18,000- 26,000 pN.nm2), support the idea that the disassembling MT is capable of generating a large mechanical force to move chromosomes during cell division. Our computational modeling offers a comprehensive quantitative platform to link molecular tubulin characteristics with the physiological behavior of MTs. The developed in silico nanoindentation method provides a powerful tool for the exploration of biomechanical properties of other cytoskeletal and multiprotein assemblies (Kononova et al. 2014).

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References
    A. Zhmurov, A., Dima, R. I., Kholodov, Y., Barsegov, V. (2010). SOP-GPU: Accelerating biomolecular simulations in the centisecond timescale using graphics processors. Proteins 78, 2984-2999.

    P. J. de Pablo, P. J., Schaap, I. A. T., MacKintosh, F. C., Schmidt, C. F. (2003). Deformation and collapse of microtubules on the nanometer scale. Phys. Rev. Lett. 91, 098101-098104.

    O. Kononova, Y. Kholodov, K. E. Theisen, K. A. Marx, R. I. Dima, F. I. Ataullakhanov, E. L. Grishchuk, and V. Barsegov (2014) Tubulin bond energies and microtubule biomechanics determined from nanoindentation in silico. J. Am. Chem. Soc. 136, 17036-17045.


Olga Kononova 1, 2
Yaroslav Kholodov2
Kelly E. Theisen3
Kenneth A. Marx1
Ruxandra I. Dima3
Fazly I. Ataullakhanov 4, 5
Ekaterina L. Grishchuk 6
Valeri Barsegov 1, 2

1Department of Chemistry
University of Massachusetts
Lowell, MA 01854, USA
2Moscow Institute of Physics and Technology
Moscow region, 141700, Russia
3Department of Chemistry
University of Cincinnati
Cincinnati, OH 45221, USA
4Center for Theoretical Problems of Physicochemical Pharmacology
RAS, Moscow 119991, Russia
5 Physics Department
Moscow State University
Moscow 119991, Russia
6Physiology Department
Perelman School of Medicine
University of Pennsylvania
Philadelphia, PA 19104

Ph: (857) 756-2070
olga_kononova@student.uml.edu