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Browsing by Author "Canner, Samuel W."
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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 Docosahexaenoic acid regulates the formation of lipid rafts: A unified view from experiment and simulation(Elsevier, 2018-10) Wassall, Stephen R.; Leng, Xiaoling; Canner, Samuel W.; Pennington, Edward Ross; Kinnun, Jacob J.; Cavazos, Andres T.; Dadoo, Sahil; Johnson, Dylan; Heberle, Frederick A.; Katsaras, John; Shaikh, Saame Raza; Physics, School of ScienceDocosahexaenoic acid (DHA, 22:6) is an n-3 polyunsaturated fatty acid (n-3 PUFA) that influences immunological, metabolic, and neurological responses through complex mechanisms. One structural mechanism by which DHA exerts its biological effects is through its ability to modify the physical organization of plasma membrane signaling assemblies known as sphingomyelin/cholesterol (SM/chol)-enriched lipid rafts. Here we studied how DHA acyl chains esterified in the sn-2 position of phosphatidylcholine (PC) regulate the formation of raft and non-raft domains in mixtures with SM and chol on differing size scales. Coarse grained molecular dynamics simulations showed that 1-palmitoyl-2-docosahexaenoylphosphatylcholine (PDPC) enhances segregation into domains more than the monounsaturated control, 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC). Solid state 2H NMR and neutron scattering experiments provided direct experimental evidence that substituting PDPC for POPC increases the size of raft-like domains on the nanoscale. Confocal imaging of giant unilamellar vesicles with a non-raft fluorescent probe revealed that POPC had no influence on phase separation in the presence of SM/chol whereas PDPC drove strong domain segregation. Finally, monolayer compression studies suggest that PDPC increases lipid-lipid immiscibility in the presence of SM/chol compared to POPC. Collectively, the data across model systems provide compelling support for the emerging model that DHA acyl chains of PC lipids tune the size of lipid rafts, which has potential implications for signaling networks that rely on the compartmentalization of proteins within and outside of rafts.