On the Structure and Flip-flop of Free Docosahexaenoic Acid in a Model Human Brain Membrane.

Among the omega-3 fatty acids, docosahexaenoic acid (DHA, sn22:6) is particularly vital in human brain cell membranes. There is considerable interest in DHA because low-level DHA has been associated with declined cognitive function and poor visual acuity. In this work, atomistic molecular dynamics simulations were used to investigate the effects of free protonated DHA (DHAP) in molar fractions of 0, 17, 30, and 38% in a realistic model of a healthy brain cell membrane comprising 26 lipid types. Numerous flip-flop events of DHAP were observed and categorized as successful or aborted. Novel use of the machine learning technique, density-based spatial clustering of applications with noise (DBSCAN), effectively identified flip-flop events by way of clustering. Our data show that increasing amounts of DHAP in the membrane disorder the bilayer packing, fluidize the membrane, and increase the rates of successful flip-flop from k = 0.2 µs-1 (17% DHAP) to 0.8 µs-1 (30% DHAP) and to 1.3 µs-1 (38% DHAP). In addition, we also provided a detailed understanding of the flip-flop mechanism of DHAP across this complex membrane. Interestingly, we noted the role of hydrogen bonds in two distinct coordinated flip-flop phenomena between two DHAP molecules: double flip-flop and assisted flip-flop. Understanding the effects of various concentrations of DHAP on the dynamics within a lipid membrane and the resulting structural properties of the membrane are important when considering the use of DHAP as a dietary supplement or as a potential therapeutic.

Effects of lipid heterogeneity on model human brain lipid membranes.

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.