The integrity of cellular membranes is critical for the functionality of axons. Failure of the axonal membranes (plasma membrane and/or myelin sheath) can be the origin of neurological diseases. The two membranes differ in the content of sphingomyelin and galactosylceramide lipids. We investigate the relation between lipid content and bilayer structural-mechanical properties, to better understand the dependency of membrane properties on lipid composition. A sphingomyelin/phospholipid/cholesterol bilayer is used to mimic a plasma membrane and a galactosylceramide/phospholipid/cholesterol bilayer to mimic a myelin sheath. Molecular dynamics simulations are performed at atomistic and coarse-grained levels to characterize the bilayers at equilibrium and under deformation. For comparison, simulations of phospholipid and phospholipid/cholesterol bilayers are also performed. The results clearly show that the bilayer biomechanical and structural features depend on the lipid composition, independent of the molecular models. Both galactosylceramide or sphingomyelin lipids increase the order of aliphatic tails and resistance to water penetration. Having 30% galactosylceramide increases the bilayers stiffness. Galactosylceramide lipids pack together via sugar-sugar interactions and hydrogen-bond phosphocholine with a correlated increase of bilayer thickness. Our findings provide a molecular insight on role of lipid content in natural membranes.

Morphological choicesAs now reported in the main text of the manuscript, given the axon cross-section and the proposed MTs densities (Bray and Bunge 1981, Fadic et al. 1985, Malbouisson et al. 1985) 19 rows of MTs were included in the axon RV, each containing two randomly placed discontinuities. The same approach was used in Peter and Mofrad (2012), Lazarus et al. (2015), Soheilypour et al. (2015). Mechanical properties of the MTs have been very well identifies by previous studies. Material properties These filaments represent the stiffest part of the cytoskeleton and the Youngs' modulus (E=830 MPa) was derived by Zhang et al. (2014) with a numerical approach and was in extremely good agreement with experiments by de Pablo et al (2003)where MTs are locally probed. In the latter study, older bending experiments (which estimate a modulus E=1 to 1.2 GPa) were considered to overestimate the material properties of MTs because they usually probe length scales much longer than the one necessary to assess material properties. Being these filaments far stiffer then the remainder of our model, it can be said that a slightly stiffer modulus would not affect the localization of strains on the membrane. Tau proteins:Morphological choices Cross-connection between microtubules (MTs) and between neurofilaments (NFs) and MTs were quantified in a seminal study by Hirokawa (1982). There, MTs crosslinks were found to be less abundant than those between neurofilaments, which were reported having a 30-50 nm spacing. Inspecting the microscopy images in the same publication, a spacing of 120 nm was chosen for our model. Previous studies have also shown, through a sensitivity study, that tau protein density does not influence the energy associated with MTs stretching. Material propertiesCompared to the MTs, the material properties of these filaments are far less studied. The properties that we chose are based on previous studies by Ahmadzadeh et al (2014,2015). In these studies the viscoelastic characteristic of these cross-links was derived from previous experimental studies. While the spring stiffness is in the range of previously tested motor proteins (kinesin stiffness = uN/m ), we agree that its viscous component is the biggest assumption behind our model, which would however would affect mostly the microtubule Bray, D. and Bunge, M.B., 1981. Serial analysis of microtubules in cultured rat sensory axons. ., 2003. Deformation and collapse of microtubules on the nanometer scale. Physical review letters, 91(9), p.098101. Hirokawa, N., 1982. Cross-linker system between neurofilaments, microtubules and membranous organelles in frog axons revealed by the quick-freeze, deep-etching method. The Journal of cell biology, 94(1), pp.129-142. Ahmadzadeh, H., Smith, D.H. and Shenoy, V.B., 2014. Viscoelasticity of tau proteins leads to strain rate-dependent breaking of microtubules during axonal stretch injury: predictions from a mathematical model. Biophysical journal, 106(5), pp.1123-1133. Ahmadzadeh, H., Smith, D.H. and Shenoy, V.B., 2015. Mech...

The use of carbon-based nanomaterials is tremendously increasing in various areas of technological, bioengineering, and biomedical applications. The functionality of carbon-based nanomaterials can be further broadened via chemical functionalization of carbon nanomaterial surfaces. On the other hand, concern is rising on possible adverse effects when nanomaterials are taken up by biological organisms. In order to contribute into understanding of interactions of carbon-based nanomaterials with biological matter, we have investigated adsorption of small biomolecules on nanomaterials using enhanced sampling molecular dynamics. The biomolecules included amino acid side chain analogues, fragments of lipids, and sugar monomers. The adsorption behavior on unstructured amorphous carbon, pristine graphene and its derivatives (such as few-layer graphene, graphene oxide, and reduced graphene oxide) as well as pristine carbon nanotubes, and those functionalized with OH – , COOH – , COO – , NH 2 – , and NH 3 + groups was investigated with respect to surface concentration. An adsorption profile, that is, the free energy as a function of distance from the nanomaterial surfaces, was determined for each molecule and surface using the Metadynamics approach. The results were analyzed in terms of chemical specificity, surface charge, and surface concentration. It was shown that although morphology of the nanomaterial has a limited effect on the adsorption properties, functionalization of the surface by various molecular groups can drastically change the adsorption behavior that can be used in the design of nanosurfaces with highly selective adsorption properties and safe for human health and environment.

Around half of the traumatic brain injuries are thought to be axonal damage. Disruption of the cellular membranes, or alternatively cytoskeletal damage has been suggested as possible injury trigger. Here, we have used molecular models to have a better insight on the structural and mechanical properties of axon sub-cellular components. We modelled myelin sheath and node of Ranvier as lipid bilayers at a coarse grained level. We built ex-novo a model for the myelin. Lipid composition and lipid saturation were based on the available experimental data. The model contains 17 different types of lipids, distributed asymmetrically between two leaflets. Molecular dynamics simulations were performed to characterize the myelin and node-of-Ranvier bilayers at equilibrium and under deformation and compared to previous axolemma simulations. We found that the myelin bilayer has a slightly higher area compressibility modulus and higher rupture strain than node of Ranvier. Compared to the axolemma in unmyelinated axon, mechanoporation occurs at 50% higher strain in the myelin and at 23% lower strain in the node of Ranvier in myelinated axon. Combining the results with finite element simulations of the axon, we hypothesizes that myelin does not rupture at the thresholds proposed in the literature for axonal injury while rupture may occur at the node of Ranvier. The findings contribute to increases our knowledge of axonal sub-cellular components and help to understand better the mechanism behind axonal brain injury.

13Traumatic brain injuries are a leading cause of morbidity and mortality worldwide. With 14 almost 50% of traumatic brain injuries being related to axonal damage, understanding the 15 nature of cellular level impairment is crucial. Experimental observations have so far led to the 16 formulation of conflicting theories regarding the cellular primary injury mechanism. 17 Disruption of the axolemma, or alternatively cytoskeletal damage has been suggested mainly 18 as injury trigger. However, mechanoporation thresholds of generic membranes seem not to 19 overlap with the axonal injury deformation range and microtubules appear too stiff and too 20 weakly connected to undergo mechanical breaking. Here, we aim to shed a light on the 21 mechanism of primary axonal injury, bridging finite element and molecular dynamics 22 simulations. Despite the necessary level of approximation, our models can accurately 23 describe the mechanical behavior of the unmyelinated axon and its membrane. More 24 importantly, they give access to quantities that would be inaccessible with an experimental 25 approach. We show that in a typical injury scenario, the axonal cortex sustains deformations 26 large enough to entail pore formation in the adjoining lipid bilayer. The observed axonal 27 deformation of 10-12% agree well with the thresholds proposed in the literature for axonal 28 injury and, above all, allow us to provide quantitative evidences that do not exclude pore 29 formation in the membrane as a result of trauma. Our findings bring to an increased 30 knowledge of axonal injury mechanism that will have positive implications for the prevention 31 and treatment of brain injuries. 33 34Traumatic brain injury (TBI) is defined as "an alteration in brain function, or other evidence 2 of brain pathology, caused by an external force". 1 In 2013 approximately 2.8 million TBI-3 related emergency department visits, hospitalization, and deaths occurred in the United 4 States. 2 In a recent study reporting the epidemiology of TBI in Europe, Peeters and coworkers 5 analyzed data from 28 studies on 16 European countries and reported an average mortality 6 rate of ≈ 11 per 100,000 population over an incidence rate of 262 per 100,000 population per 7year. 3 Diffuse axonal injury (DAI), a multifocal damage to white matter axons, is the most 8 common consequence of TBIs of all severities including mild TBIs or concussions. 4 Invisible 9 to conventional brain imaging, DAI can only be histologically diagnosed and its hallmark is 10 the presence of axonal swellings or retraction balls observable under microscopic 11 examination. 5 12 13Considerable research effort has been put into the understanding of the primary effects of 14 trauma onto the neurons. To define an axonal injury trigger, nervous tissues and neuronal 15 cultures have been subjected to dynamic loads leading to several hypotheses regarding the 16 cell injury mechanism. Mechanoporation (i.e. the generation of membrane pores due to 17 mechanical deformation) of the axolemma has been his...