Molecular dynamics study of stiffness and rupture of axonal membranes

Abstract

Diffuse axon injury (DAI) accounts for approximately half of traumatic brain injuries, yet its underlying mechanism remains unclear. Different theories exist about the mechanism of DAI, among which, one hypothesis states that membrane poration of the axons initiates DAI. To investigate the hypothesis, molecular models of axonal membranes, incorporating 25 different lipids distributed asymmetrically in the leaflets, were developed using molecular dynamics simulations and a coarse-grain description. Employing a bottom-top approach, these models were coupled with a finite element model representing the axon at the cell level. Different concentrations of proteins were embedded inside the model to represent the node-of-Ranvier and unmyelinated axonal membrane. The bilayers were investigated in equilibration and under deformation to characterize the structural and mechanical properties of the membranes and comparisons were made with other subcellular parts, particularly myelin. Results indicate that pore formation in the node-of-Ranvier occurs at a lower rupture strain compared to other axolemma models, whereas myelin poration exhibits the highest rupture strains among the investigated models. The observed rupture strain for the node-of-Ranvier aligns with experimental studies, indicating a threshold for injury at axonal strains exceeding 10-13% depending on the strain rate. This study enhances our understanding of DAI at a multi-scale level by revealing the mechanical properties of axonal membranes under both biological conditions and during injury.