Conformational properties of interacting neurofilaments: Monte Carlo simulations of cylindrically grafted apposing neurofilament brushes

Abstract

Neurofilaments are essential cytoskeletal filaments that impart mechanical stability to axons. They are mostly assembled from three neurofilament proteins that form the core of the filament and its sidearms. Adjacent neurofilaments interact with each other through their apposing sidearms and attain unique conformations depending on the ionic condition, phosphorylation state, and interfilament separations. To understand the conformational properties of apposing sidearms under various conditions and gain insight into interfilament interactions, we performed Monte Carlo simulations of neurofilament pairs. We employed a sequence-based coarse-grained model of apposing NF sidearms that are end-tethered to cylindrical geometries according to the stoichiometry of the three neurofilament subunits. Monte Carlo simulations were conducted under different conditions such as phosphorylation state, ionic condition, and interfilament separations. Under saltfree conditions, apposing sidearms are found to adopt mutually excluding stretched but bent away conformations that are reminiscent of a repulsive type of interaction. Under physiological conditions, apposing sidearms are found to be in a coiled conformation, suggesting a short-range steric repulsive type of interaction. Increased sidearm mutual interpenetration and a simultaneous decrease in the individual brush heights were observed as the interfilament separation was reduced from 60 to 40 nm. The observed conformations suggest entropic interaction as a likely mechanism for sidearm-mediated interfilament interactions under physiological conditions. Electronic supplementary materialThe online version of this article

Neurofilaments Function as Shock Absorbers: Compression Response Arising from Disordered Proteins

“…t c o n c e n t r a t i o n ( m M ) (a) NF-L inter-filament spacing vs. monovalent salt concentration of NF-L at: 0 % PEG ( ), 20 % PEG (•), andEDTA assembly buffer with 0 % PEG ( ). Increasing concentrations beyond 100mM do not significantly modify the stress response, in agreement with previous simulations[36]. The inter-filament distance measured in NF-L networks formed with EDTA buffer show that the bridging mechanism does not require divalent salts.…”

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“…The inner layer corona is composed of the short NF-L tails while NF-H tails are repelled farther away from the corona into the outer layer. Since the tails within the outer layer are less dense, they assume a flower-like conformation (29,38,39). However, this picture does not agree with the NF-LM tails organization.…”

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