Computational Investigation of the Mechanism Behind Sidearm-Mediated Neurofilament Interaction

Abstract

Neurofilaments (NFs) are essential cytoskeletal filaments that determine the axonal caliber and impart mechanical integrity to the nerve cells. They are assembled from three distinct molecular weight proteins - neurofilament light (NF-L), medium (NF-M), and heavy (NF-H). The three proteins are bound to each other laterally forming 10-nm filamentous rods along with sidearm extensions that vary in the number and sequences of amino acid residues. Additionally, the polypeptide chains attain negative charges through serine phosphorylation of the Lys-Ser-Pro (KSP) repeat motifs that are particularly found in the NF-H and NF-M sidearms. The NF sidearms are known to mediate the interaction between neurofilaments, and a number of models have been proposed in the literature for describing the interfilament interactions. However, the precise mechanism by which NF sidearms regulate NF-NF interaction remains unsettled. To understand the exact nature of sidearm-mediated interactions, we employed the polymer brush model of NF (Chang et al. J. Mol. Biol. (2009) 391:648-660). The model incorporates the stoichiometry and charge distribution of NF sidearms, where the latter arises from the ionizable amino acids as well as the KSP repeat motifs of the polypeptide chains. By using the NF brush model, we performed Monte Carlo simulations to investigate the interaction between neurofilaments under various conditions. We present the analyses of Monte Carlo simulations that are carried out to reveal the underlying mechanism behind interfilament interactions.