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.
Highlights
Being able to control protein-based cellular functions with an electromagnetic field could open an exciting spectrum of possibilities for advancing biotechnological processes
Taking as an example the 1TUB tubulin structure, we found that while a relative content of acidic residues is similar in tubulin versus the average from the PISCES set, tubulin contains fewer basic residues than an average protein
It is worth noting that a large fraction of electric charge of tubulin is due to the unstructured and highly flexible C-terminal tail (CTT)
Summary
Being able to control protein-based cellular functions with an electromagnetic field could open an exciting spectrum of possibilities for advancing biotechnological processes. To overcome thermal noise effects and avoid heating side-effects, short (MV/m) electric pulses lend themselves as a suitable form of the electromagnetic field that can be utilized to modulate protein function[6,7] It has been demonstrated through molecular dynamics simulations that EFs can affect conformation of pancreatic trypsin inhibitor[8], insulin[9,10,11], lysozyme[12,13,14,15], β-amyloid and amyloid forming peptides[16,17], and soybean hydrophobic protein[18]. It is already known that various stabilizing/ destabilizing tubulin-binding drugs such as taxanes, colchicines, and vinca alkaloids, bind to different sites on the tubulin dimer, modulating microtubule-based processes[53] This type of binding is assumed to be based on purely electrostatic interactions like those employed in the recognition between proteins[2]. In this paper, we cast light on the mechanism of direct EF action on tubulin at the molecular level
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