Effects of molecular model, ionic strength, divalent ions, and hydrophobic interaction on human neurofilament conformation

Abstract

The present study examines the effects of the model dependence, ionic strength, divalent ions, and hydrophobic interaction on the structural organization of the human neurofilament (NF) brush, using canonical ensemble Monte Carlo (MC) simulations of a coarse-grained model with the amino-acid resolution. The model simplifies the interactions between the NF core and the sidearm or between the sidearms by the sum of excluded volume, electrostatic, and hydrophobic interactions, where both monovalent salt ions and solvents are implicitly incorporated into the electrostatic interaction potential. Several important observations are made from the MC simulations of the coarse-grained model NF systems. First, the mean-field type description of monovalent salt ions works reasonably well in the NF system. Second, the manner by which the NF sidearms are arranged on the surface of the NF backbone core has little influence on the lateral extension of NF sidearms. Third, the lateral extension of the NF sidearms is highly affected by the ionic strength of the system: at low ionic strength, NF-M is most extended but at high ionic strength, NF-H is more stretched out because of the effective screening of the electrostatic interaction. Fourth, the presence of Ca(2+) ions induces the attraction between negatively charged residues, which leads to the contraction of the overall NF extension. Finally, the introduction of hydrophobic interaction does not change the general structural organization of the NF sidearms except that the overall extension is contracted.

Neurofilament networks: Salt-responsive hydrogels with sidearm-dependent phase behavior

“…Interestingly, and in support of this salt-dependent sidearm behavior, Lee et al show that for ionic strengths > 50 mM, NF-H is now more extended than NF-M. This is in nice agreement with the larger measured spacings for the copolymer NF-LH systems and the --‖ in the ternary NF-LMH systems [44].…”

“…Furthermore, Lee et al predict by molecular modeling of the effects of ionic strength on NF architecture that the sidearms are highly extended at non-physiological low salt (1 mM and 10 mM, compared to 100 mM), where NF-M is much more extended than NF-H. This change in sidearm extension at C S characteristic of the B G phase could explain why the onset of the I G phase is significantly more delayed for NF-M than for NF-H [44].…”

Site-Specific Modulation of Charge Controls the Structure and Stimulus Responsiveness of Intrinsically Disordered Peptide Brushes

“…For the non-phosphorylated side arm domain, the R g is expected to remain constant up to an ionic strength of approximately 40 mM, followed by a small increase. 46 …”

Order and disorder in intermediate filament proteins

“…The short ($2) nm distance between adjacent tails on the backbone circumference gives rise to intra-filament tail-to-tail interactions. Furthermore, intra-filament tail-to-backbone interactions, and internal interactions within the single tail, must also be taken into account [133,134,170].…”