693 research outputs found
Model of ionic currents through microtubule nanopores and the lumen
It has been suggested that microtubules and other cytoskeletal filaments may
act as electrical transmission lines. An electrical circuit model of the
microtubule is constructed incorporating features of its cylindrical structure
with nanopores in its walls. This model is used to study how ionic conductance
along the lumen is affected by flux through the nanopores when an external
potential is applied across its two ends. Based on the results of Brownian
dynamics simulations, the nanopores were found to have asymmetric inner and
outer conductances, manifested as nonlinear IV curves. Our simulations indicate
that a combination of this asymmetry and an internal voltage source arising
from the motion of the C-terminal tails causes a net current to be pumped
across the microtubule wall and propagate down the microtubule through the
lumen. This effect is demonstrated to enhance and add directly to the
longitudinal current through the lumen resulting from an external voltage
source, and could be significant in amplifying low-intensity endogenous
currents within the cellular environment or as a nano-bioelectronic device.Comment: 43 pages, 6 figures, revised versio
Tubulin response to intense nanosecond-scale electric field in molecular dynamics simulation
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
Cytoplasmic dynein binding, run length, and velocity are guided by long-range electrostatic interactions
Dyneins are important molecular motors involved in many essential biological processes, including cargo transport along microtubules, mitosis, and in cilia. Dynein motility involves the coupling of microtubule binding and unbinding to a change in the configuration of the linker domain induced by ATP hydrolysis, which occur some 25 nm apart. This leaves the accuracy of dynein stepping relatively inaccurate and susceptible to thermal noise. Using multi-scale modeling with a computational focusing technique, we demonstrate that the microtubule forms an electrostatic funnel that guides the dynein’s microtubule binding domain (MTBD) as it finally docks to the precise, keyed binding location on the microtubule. Furthermore, we demonstrate that electrostatic component of the MTBD’s binding free energy is linearly correlated with the velocity and run length of dynein, and we use this linearity to predict the effect of mutating each glutamic and aspartic acid located in MTBD domain to alanine. Lastly, we show that the binding of dynein to the microtubule is associated with conformational changes involving several helices, and we localize flexible hinge points within the stalk helices. Taken all together, we demonstrate that long range electrostatic interactions bring a level of precision to an otherwise noisy dynein stepping process
A Bio-Polymer Transistor: Electrical Amplification by Microtubules
Microtubules (MTs) are important cytoskeletal structures, engaged in a number
of specific cellular activities, including vesicular traffic, cell
cyto-architecture and motility, cell division, and information processing
within neuronal processes. MTs have also been implicated in higher neuronal
functions, including memory, and the emergence of "consciousness". How MTs
handle and process electrical information, however, is heretofore unknown. Here
we show new electrodynamic properties of MTs. Isolated, taxol-stabilized
microtubules behave as bio-molecular transistors capable of amplifying
electrical information. Electrical amplification by MTs can lead to the
enhancement of dynamic information, and processivity in neurons can be
conceptualized as an "ionic-based" transistor, which may impact among other
known functions, neuronal computational capabilities.Comment: This is the final submitted version. The published version should be
downloaded from Biophysical Journa
Atomistic molecular dynamics simulations of tubulin heterodimers explain the motion of a microtubule
Microtubules are essential parts of the cytoskeleton that are built by polymerization of tubulin heterodimers into a hollow tube. Regardless that their structures and functions have been comprehensively investigated in a modern soft matter, it is unclear how properties of tubulin heterodimer influence and promote the self-assembly. A detailed knowledge of such structural mechanisms would be helpful in drug design against neurodegenerative diseases, cancer, diabetes etc. In this work atomistic molecular dynamics simulations were used to investigate the fundamental dynamics of tubulin heterodimers in a sheet and a short microtubule utilizing well-equilibrated structures. The breathing motions of the tubulin heterodimers during assembly show that the movement at the lateral interface between heterodimers (wobbling) dominates in the lattice. The simulations of the protofilament curvature agrees well with recently published experimental data, showing curved protofilaments at polymerization of the microtubule plus end. The tubulin heterodimers exposed at the microtubule minus end were less curved and displayed altered interactions at the site of sheet closure around the outmost heterodimers, which may slow heterodimer binding and polymerization, providing a potential explanation for the limited dynamics observed at the minus end
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