- Browse by Author
Browsing by Author "Feller, Scott E."
Now showing 1 - 4 of 4
Results Per Page
Sort Options
Item All n-3 PUFA are not the same: MD simulations reveal differences in membrane organization for EPA, DHA and DPA(Elsevier, 2018) Leng, Xiaoling; Kinnun, Jacob J.; Cavazos, Andres T.; Canner, Samuel W.; Shaikh, Saame Raza; Feller, Scott E.; Wassall, Stephen R.; Physics, School of ScienceEicosapentaenoic (EPA, 20:5), docosahexaenoic (DHA, 22:6) and docosapentaenoic (DPA, 22:5) acids are omega-3 polyunsaturated fatty acids (n-3 PUFA) obtained from dietary consumption of fish oils that potentially alleviate the symptoms of a range of chronic diseases. We focus here on the plasma membrane as a site of action and investigate how they affect molecular organization when taken up into a phospholipid. All atom MD simulations were performed to compare 1-stearoyl-2-eicosapentaenoylphosphatylcholine (EPA-PC, 18:0–20:5PC), 1-stearoyl-2-docosahexaenoylphosphatylcholine (DHA-PC, 18:0–22:6PC), 1-stearoyl-2-docosapentaenoylphosphatylcholine (DPA-PC, 18:0–22:5PC) and, as a monounsaturated control, 1-stearoyl-2-oleoylphosphatidylcholine (OA-PC, 18:0–18:1PC) bilayers. They were run in the absence and presence of 20 mol% cholesterol. Multiple double bonds confer high disorder on all three n-3 PUFA. The different number of double bonds and chain length for each n-3 PUFA moderates the reduction in membrane order exerted (compared to OA-PC, 𝑆̅𝐶𝐷 = 0.152). EPA-PC (𝑆̅𝐶𝐷 = 0.131) is most disordered, while DPA-PC ( 𝑆̅𝐶𝐷 = 0.140) is least disordered. DHA-PC (𝑆̅𝐶𝐷 = 0.139) is, within uncertainty, the same as DPA-PC. Following the addition of cholesterol, order in EPA-PC (𝑆̅𝐶𝐷 = 0.169), DHA-PC (𝑆̅𝐶𝐷 = 0.178) and DPA-PC (𝑆̅𝐶𝐷 = 0.182) is increased less than in OA-PC (𝑆̅𝐶𝐷 = 0.214). The high disorder of n-3 PUFA is responsible, preventing the n-3 PUFA-containing phospholipids from packing as close to the rigid sterol as the monounsaturated control. Our findings establish that EPA, DHA and DPA are not equivalent in their interactions within membranes, which possibly contributes to differences in clinical efficacy.Item Interaction of α-tocopherol with a polyunsaturated lipid studied by MD simulations(Office of the Vice Chancellor for Research, 2013-04-05) Leng, Xiaoling; Williams, Justin A.; Marquardt, Drew; Kučerka, Norbert; Katsaras, John; Atkinson, Jeffrey; Harroun, Thad A.; Feller, Scott E.; Wassall, Stephen R.Polyunsaturated phospholipids are essential components of neural membranes and their effect on membrane architecture is proposed to be the molecular origin of a myriad of health benefits. A downside of polyunsaturated phospholipids is that they are highly susceptible to oxidation due to the presence of multiple double bonds. α-Tocopherol is the most biologically active component in a family of phenolic compounds that comprise vitamin E, which is the major lipid soluble antioxidant in cell membranes. To investigate whether α-tocopherol preferentially interacts with polyunsaturated phospholipids to optimize protection against oxidation, we performed MD simulations on 1-stearoyl-2-docosahexaenoylphosphatiylcholine (SDPC, 18:0-22:6PC) and 1-stearoyl-2-oleoylphosphatidylcholine (SOPC, 18:0-18:1PC) bilayers containing α-tocopherol. SDPC with a docosahexaenoyl sn-2 chain is polyunsaturated, while SOPC with an oleoyl sn-2 chain serves as a monounsaturated control. The simulations were run under constant pressure for 200 ns on a system that comprised 80 phospholipid molecules, 20 α-tocopherol molecules and 2165 water molecules. We discovered significant differences between the two systems. Analysis of the simulations indicates that the α-tocopherol has a strong interaction with the polyunsaturated fatty acid. The flip-flop of α-tocopherol across the bilayer is also much faster in SDPC than in SOPC. Solid state NMR, neutron scattering and complementary experiments are now underway to test the predictions from the MD simulations.Item α-Tocopherol is well designed to protect polyunsaturated fatty acids(Office of the Vice Chancellor for Research, 2014-04-11) Leng, Xiaoling; Williams, Justin A.; Marquardt, Drew; Kučerka, Norbert; Katsaras, John; Atkinson, Jeffrey; Harroun, Thad A.; Feller, Scott E.; Wassall, Stephen R.Polyunsaturated fatty acids (PUFA) are an influential constituent in cell membranes, but are extremely vulnerable to oxidation. The presumptive role for α-tocopherol (α-toc), the molecular form of vitamin E retained by the human body, is to protect PUFA-containing lipids from oxidation. To investigate whether α-toc preferentially interacts with PUFA in support of this function, we performed MD simulations on lipid bilayers composed of 1-stearoyl-2-docosahexaenoylphosphatidylcholine (SDPC, 18:0-22-6PC) and 1-stearoyl-2-oleoylphosphatidylcholine (SOPC, 18:0-18:1PC) in the presence of α-toc. SDPC with docosahexaenoic acid (DHA) for the sn-2 chain is polyunsaturated, while SOPC with oleic acid (OA) for the sn-2 chain serves as a monounsaturated control. The simulations were run at 37 °C under constant pressure for 200 ns on a system that comprised 80 phospholipid molecules, 20 α-toc molecules and 2165 water molecules. In qualitative agreement with our results from solid state 2H NMR and neutron scattering experiments, the simulations show that α-toc increases order inside the bilayer and that the chromanol headgroup sits near the surface in both SDPC and SOPC. Analyses of the density distribution of the lipid chains relative to α-toc show that the α-toc’s chromanol headgroup, the part of the molecule that protects against oxidation, would have more chance to interact with PUFA chains than saturated chains. A major prediction from our simulations is that α-toc undergoes flip-flop across the bilayer and that the rate is an order of magnitude greater in SDPC than SOPC. This is a remarkable finding that reveals a possible mechanism by which the chromanol group would not only wait at the membrane surface but would also patrol the membrane interior to meet lipid radicals and terminate the chain reaction by which lipid peroxidation proceeds.Item α-Tocopherol Is Well Designed to Protect Polyunsaturated Phospholipids: MD Simulations.(Elsevier, 2015-10-20) Leng, Xiaoling; Kinnun, Jacob J.; Marquardt, Drew; Ghefli, Mikel; Kučerka, Norbert; Katsaras, John; Atkinson, Jeffrey; Harroun, Thad A.; Feller, Scott E.; Wassall, Stephen R.; Department of Physics, School of ScienceThe presumptive function for alpha-tocopherol (αtoc) in membranes is to protect polyunsaturated lipids against oxidation. Although the chemistry of the process is well established, the role played by molecular structure that we address here with atomistic molecular-dynamics simulations remains controversial. The simulations were run in the constant particle NPT ensemble on hydrated lipid bilayers composed of SDPC (1-stearoyl-2-docosahexaenoylphosphatidylcholine, 18:0-22:6PC) and SOPC (1-stearoyl-2-oleoylphosphatidylcholine, 18:0-18:1PC) in the presence of 20 mol % αtoc at 37°C. SDPC with SA (stearic acid) for the sn-1 chain and DHA (docosahexaenoic acid) for the sn-2 chain is representative of polyunsaturated phospholipids, while SOPC with OA (oleic acid) substituted for the sn-2 chain serves as a monounsaturated control. Solid-state 2H nuclear magnetic resonance and neutron diffraction experiments provide validation. The simulations demonstrate that high disorder enhances the probability that DHA chains at the sn-2 position in SDPC rise up to the bilayer surface, whereby they encounter the chromanol group on αtoc molecules. This behavior is reflected in the van der Waals energy of interaction between αtoc and acyl chains, and illustrated by density maps of distribution for acyl chains around αtoc molecules that were constructed. An ability to more easily penetrate deep into the bilayer is another attribute conferred upon the chromanol group in αtoc by the high disorder possessed by DHA. By examining the trajectory of single molecules, we found that αtoc flip-flops across the SDPC bilayer on a submicrosecond timescale that is an order-of-magnitude greater than in SOPC. Our results reveal mechanisms by which the sacrificial hydroxyl group on the chromanol group can trap lipid peroxyl radicals within the interior and near the surface of a polyunsaturated membrane. At the same time, water-soluble reducing agents that regenerate αtoc can access the chromanol group when it locates at the surface.