Tubulin's Response to External Electric Fields by Molecular Dynamics Simulations

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2018 Sep 20

PMID 30231050

Citations 15

Authors

Joshua J Timmons

Jordane Preto

Jack A Tuszynski

Eric T Wong

Affiliations

Soon will be listed here.

Abstract

Tubulin heterodimers are the building blocks of microtubules and disruption of their dynamics is exploited in the treatment of cancer. Electric fields at certain frequencies and magnitudes are believed to do the same. Here, the tubulin dimer's response to external electric fields was determined by atomistic simulation. External fields from 50 to 750 kV/cm, applied for 10 ns, caused significant conformational rearrangements that were dependent upon the field's directionality. Charged and flexible regions, including the α:H1-B2 loop, β:M-loop, and C-termini, were susceptible. Closer inspection of the α:H1-B2 loop in lower strength fields revealed that these effects were consistent and proportional to field strength, and the findings indicate that external electric fields modulate the stability of microtubules through conformational changes to key loops involved in lateral contacts. We also find evidence that tubulin's curvature and elongation are affected, and external electric fields may bias tubulin towards depolymerization.

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References

Thompson G, Roth C, Tolstykh G, Kuipers M, Ibey B . Disruption of the actin cortex contributes to susceptibility of mammalian cells to nanosecond pulsed electric fields. Bioelectromagnetics. 2014; 35(4):262-72. DOI: 10.1002/bem.21845. View

Li H, DeRosier D, Nicholson W, Nogales E, Downing K . Microtubule structure at 8 A resolution. Structure. 2002; 10(10):1317-28. DOI: 10.1016/s0969-2126(02)00827-4. View

Shi Y, Xia Z, Zhang J, Best R, Wu C, Ponder J . The Polarizable Atomic Multipole-based AMOEBA Force Field for Proteins. J Chem Theory Comput. 2013; 9(9):4046-4063. PMC: 3806652. DOI: 10.1021/ct4003702. View

Stupp R, Wong E, Kanner A, Steinberg D, Engelhard H, Heidecke V . NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer. 2012; 48(14):2192-202. DOI: 10.1016/j.ejca.2012.04.011. View

Stacey M, Fox P, Buescher S, Kolb J . Nanosecond pulsed electric field induced cytoskeleton, nuclear membrane and telomere damage adversely impact cell survival. Bioelectrochemistry. 2011; 82(2):131-4. DOI: 10.1016/j.bioelechem.2011.06.002. View

Freedman H, Luchko T, Luduena R, Tuszynski J . Molecular dynamics modeling of tubulin C-terminal tail interactions with the microtubule surface. Proteins. 2011; 79(10):2968-82. DOI: 10.1002/prot.23155. View

Carr L, Bardet S, Burke R, Arnaud-Cormos D, Leveque P, OConnor R . Calcium-independent disruption of microtubule dynamics by nanosecond pulsed electric fields in U87 human glioblastoma cells. Sci Rep. 2017; 7:41267. PMC: 5259788. DOI: 10.1038/srep41267. View

Wang Z, Sheetz M . The C-terminus of tubulin increases cytoplasmic dynein and kinesin processivity. Biophys J. 2000; 78(4):1955-64. PMC: 1300788. DOI: 10.1016/S0006-3495(00)76743-9. View

Janke C, Bulinski J . Post-translational regulation of the microtubule cytoskeleton: mechanisms and functions. Nat Rev Mol Cell Biol. 2011; 12(12):773-86. DOI: 10.1038/nrm3227. View

10.

Beebe S, White J, Blackmore P, Deng Y, Somers K, Schoenbach K . Diverse effects of nanosecond pulsed electric fields on cells and tissues. DNA Cell Biol. 2003; 22(12):785-96. DOI: 10.1089/104454903322624993. View

11.

Ren Z, Chen X, Cui G, Yin S, Chen L, Jiang J . Nanosecond pulsed electric field inhibits cancer growth followed by alteration in expressions of NF-κB and Wnt/β-catenin signaling molecules. PLoS One. 2013; 8(9):e74322. PMC: 3775773. DOI: 10.1371/journal.pone.0074322. View

12.

Hekstra D, White K, Socolich M, Henning R, Srajer V, Ranganathan R . Electric-field-stimulated protein mechanics. Nature. 2016; 540(7633):400-405. PMC: 5730412. DOI: 10.1038/nature20571. View

13.

Isozaki N, Ando S, Nakahara T, Shintaku H, Kotera H, Meyhofer E . Control of microtubule trajectory within an electric field by altering surface charge density. Sci Rep. 2015; 5:7669. PMC: 4286733. DOI: 10.1038/srep07669. View

14.

Kirson E, Gurvich Z, Schneiderman R, Dekel E, Itzhaki A, Wasserman Y . Disruption of cancer cell replication by alternating electric fields. Cancer Res. 2004; 64(9):3288-95. DOI: 10.1158/0008-5472.can-04-0083. View

15.

Stupp R, Taillibert S, Kanner A, Read W, Steinberg D, Lhermitte B . Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial. JAMA. 2017; 318(23):2306-2316. PMC: 5820703. DOI: 10.1001/jama.2017.18718. View

16.

Yin S, Chen X, Hu C, Zhang X, Hu Z, Yu J . Nanosecond pulsed electric field (nsPEF) treatment for hepatocellular carcinoma: a novel locoregional ablation decreasing lung metastasis. Cancer Lett. 2014; 346(2):285-91. DOI: 10.1016/j.canlet.2014.01.009. View

17.

Gera N, Yang A, Holtzman T, Lee S, Wong E, Swanson K . Tumor treating fields perturb the localization of septins and cause aberrant mitotic exit. PLoS One. 2015; 10(5):e0125269. PMC: 4444126. DOI: 10.1371/journal.pone.0125269. View

18.

Garon E, Sawcer D, Vernier P, Tang T, Sun Y, Marcu L . In vitro and in vivo evaluation and a case report of intense nanosecond pulsed electric field as a local therapy for human malignancies. Int J Cancer. 2007; 121(3):675-82. DOI: 10.1002/ijc.22723. View

19.

Salari V, Barzanjeh S, Cifra M, Simon C, Scholkmann F, Alirezaei Z . Electromagnetic ﬁelds and optomechanics in cancer diagnostics and treatment. Front Biosci (Landmark Ed). 2018; 23(8):1391-1406. DOI: 10.2741/4651. View

20.

Okada Y, Hirokawa N . Mechanism of the single-headed processivity: diffusional anchoring between the K-loop of kinesin and the C terminus of tubulin. Proc Natl Acad Sci U S A. 2000; 97(2):640-5. PMC: 15383. DOI: 10.1073/pnas.97.2.640. View