Abstract
Cell membranes naturally contain a heterogeneous lipid distribution. However, homogeneous bilayers are commonly preferred and utilised in computer simulations due to their relative simplicity, and the availability of lipid force field parameters. Recently, experimental lipidomics data for the human brain cell membranes under healthy and Alzheimer's disease (AD) conditions were investigated, since disruption to the lipid composition has been implicated in neurodegenerative disorders, including AD [R. B. Chan et al., J. Biol. Chem., 2012, 287, 2678-2688]. In order to observe the effects of lipid complexity on the various bilayer properties, molecular dynamics simulations were used to study four membranes with increasing heterogeneity: a pure POPC membrane, a POPC and cholesterol membrane in a 1 : 1 ratio (POPC-CHOL), and to our knowledge, the first realistic models of a healthy brain membrane and an Alzheimer's diseased brain membrane. Numerous structural, interfacial, and dynamical properties, including the area per lipid, interdigitation, dipole potential, and lateral diffusion of the two simple models, POPC and POPC-CHOL, were analysed and compared to those of the complex brain models consisting of 27 lipid components. As the membranes gain heterogeneity, a number of alterations were found in the structural and dynamical properties, and more significant differences were observed in the lateral diffusion. Additionally, we observed snorkeling behaviour of the lipid tails that may play a role in the permeation of small molecules across biological membranes. In this work, atomistic description of realistic brain membrane models is provided, which can add insight towards the permeability and transport pathways of small molecules across these membrane barriers.
Highlights
IntroductionIn order to observe the effects of lipid complexity on the various bilayer properties, molecular dynamics simulations were used to study four membranes with increasing heterogeneity: a pure POPC membrane, a POPC and cholesterol membrane in a 1 : 1 ratio (POPC–CHOL), and to our knowledge, the first realistic models of a healthy brain membrane and an Alzheimer’s diseased brain membrane
Interfacial, and dynamical properties, including the area per lipid, interdigitation, dipole potential, and lateral diffusion of the two simple models, POPC and POPC–CHOL, were analysed and compared to those of the complex brain models consisting of 27 lipid components
We have conducted atomistic simulations to compare between bilayers containing simplistic (POPC and POPC–CHOL) and complex (BH800/BH and BAD800/BAD) lipid compositions
Summary
In order to observe the effects of lipid complexity on the various bilayer properties, molecular dynamics simulations were used to study four membranes with increasing heterogeneity: a pure POPC membrane, a POPC and cholesterol membrane in a 1 : 1 ratio (POPC–CHOL), and to our knowledge, the first realistic models of a healthy brain membrane and an Alzheimer’s diseased brain membrane. The models used range in lipid composition from pure 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)[39,40,41,42] to mixtures of up to five different lipid species (including cholesterol)[43,44] to complex realistic lipid mixtures.[45,46] In the current work, all-atom classical molecular dynamics (MD) simulations were used to investigate the effects of increasing lipid complexity on the bilayer structure, lipid dynamics, and dipole potential. We present the first heterogeneous brain cell models consisting of 27 lipid components in an effort to mimic the experimental compositions identified by Chan et al.[47] (Fig. 1 and Table 1)
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