Tubulin response to intense nanosecond-scale electric field in molecular dynamics simulation

Abstract

Intense pulsed electric fields are known to act at the cell membrane level and are already being exploited in biomedical and biotechnological applications. However, it is not clear if electric pulses within biomedically-attainable parameters could directly influence intra-cellular components such as cytoskeletal proteins. If so, a molecular mechanism of action could be uncovered for therapeutic applications of such electric fields. To help clarify this question, we first identified that a tubulin heterodimer is a natural biological target for intense electric fields due to its exceptional electric properties and crucial roles played in cell division. Using molecular dynamics simulations, we then demonstrated that an intense - yet experimentally attainable - electric field of nanosecond duration can affect the bβ-tubulin’s C-terminus conformations and also influence local electrostatic properties at the GTPase as well as the binding sites of major tubulin drugs site. Our results suggest that intense nanosecond electric pulses could be used for physical modulation of microtubule dynamics. Since a nanosecond pulsed electric field can penetrate the tissues and cellular membranes due to its broadband spectrum, our results are also potentially significant for the development of new therapeutic protocols.

Molecular dynamics simulation of the nanosecond pulsed electric field effect on kinesin nanomotor

“…The kinesin dipole moment is pointing towards tubulin body (Fig. 2i–p), which has an overall negative charge 20 , as would be predicted by simple electrostatics. However, the kinesin net charge is also negative (−5 e for pH 7 - see Supplementary information S1, section Kinesin charge analysis ), which would suggest repulsive forces from tubulin, pointing to an intricate complexity of the kinesin-tubulin electrostatic interaction.…”

“…In principle, there is always a possibility to perform calculations on a longer time scale, on larger molecular systems or with higher physical accuracy. The time scale of our current simulations was 30 ns (three replicates for each condition), and the full atom molecular system was a kinesin motor domain docked on single tubulin - analyses of comparable times scale and molecular size are common in this field 20–22 . While we consider these settings to be appropriate for the first solid assessment of ns electric field effect on kinesin nanomotor, we are aware of several avenues for future work.…”

“…A way to predict if electric field (EF) is able to affect kinesin at this time scale and in what manner, is to perform molecular dynamics simulation where electric field is applied in the system 19 . In this way, the response of other protein structures to EF has been already probed 20–23 . It has been demonstrated that EF can affect conformation of pancreatic trypsin inhibitor 24 , insulin 25–27 , lysozyme 28–31 , β -amyloid and amyloid forming peptides 32,33 , and soybean hydrophobic protein 34 .…”

Intense Pulsed Electric Fields Denature Urease Protein

“…Several articles have suggested that electric fields affect cell activity, and most of the proposed mechanisms are supported by numerical calculations. 9,11,[13][14][15][16][17] There are several applications for proteins exposed to high electric fields; for example, controlling intracellular electric fields may enable the manipulation of cell activities such as cell division, which may suppress tumor growth. 15,18 A previous study reported that a bacterial spore wall composed of peptidoglycan was damaged by intense pulsed electric fields with an intensity of 7.5 kV/cm.…”

2 MV/cm Pulsed Electric Fields Promote Transthyretin Amyloid Disintegration

“…Because it is technically difficult to apply strong electric fields to liquid samples, most previous studies have used numerical calculations. 17–19 According to such calculations, proteins change their three-dimensional structures under a static electric field of 1 MV/cm. Therefore, we focused on amyloid destruction theory, which speculates that amyloid is destroyed under fields stronger than 1 MV/cm which last longer than 400 ns.…”