All n-3 PUFA are not the same: MD simulations reveal differences in membrane organization for EPA, DHA and DPA

Abstract

Eicosapentaenoic (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.