The effect of resorcinolic lipids on biological membranes Magdalena Siwko

Resorcinolic lipids Found in higher plants (cashew nut, Ginkgo biloba, wheat bran, rye, barley), lower plants (algae, mosses, fungi), microbial organisms (bacteria) Tail length (11-25) and degree of unsaturation (0-4) varies. Very low critical micelle concentration (CMC) M Potential applications: medicine, nutrition, agriculture Found in higher plants (cashew nut, Ginkgo biloba, wheat bran, rye, barley), lower plants (algae, mosses, fungi), microbial organisms (bacteria) Tail length (11-25) and degree of unsaturation (0-4) varies. Very low critical micelle concentration (CMC) M Potential applications: medicine, nutrition, agriculture

Biological activity of resorcinols  Bacteriostatic and fungistatic activity  Non-toxic to higher animals  Protect cellular lipids from oxidation processes  Bacteriostatic and fungistatic activity  Non-toxic to higher animals  Protect cellular lipids from oxidation processes On membranes: -pre-incorporated increase the resistance of the liposome to water and small solutes - incorporated into the suspension of liposomes increase a release of ions, small solutes such as glucose, change transport of water - ” surfactant-like effect ” On membranes: -pre-incorporated increase the resistance of the liposome to water and small solutes - incorporated into the suspension of liposomes increase a release of ions, small solutes such as glucose, change transport of water - ” surfactant-like effect ”

Questions: How resorcinolic lipids affect phospholipid bilayers? Is this dependent on the length of alkyl tail? How do resorcinols distribute within a DMPC bilayer? How resorcinolic lipids affect phospholipid bilayers? Is this dependent on the length of alkyl tail? How do resorcinols distribute within a DMPC bilayer?

Bilayer formation in water 64 RES19 64 RES11 64 DMPC DMPC + RES19 DMPC + RES11 DMPC + RES25 ~30-35 SPC/lipid Temperature: 323K 25-30mol% 28RES : 64DMPC or 112 RES : 256 DMPC

Starting structure Bilayer in the gel-phase 20 ns Spontaneous Aggregation of Resorcinol

Bilayer formation RES19/DMPC

Mass density distribution water phosphoryl RES RES-OH carbonyl DMPC Pure DMPC DMPC+RES19 DMPC+RES25 DMPC+RES11

Resorcinols induce packing of lipid tails

Summary Bilayer formation largely unaffected by resorcinol Asymmetric distribution between leaflets (cluster formation) but no clear domains Resorcinols increase order parameters Interaction of RES hydroxyl groups with DMPC glycerol the ester groups

Incorporation of resorcinolic lipids in the DMPC bilayer DMPCRES19RES11RES25 30mol% (21RES:64DMPC or 112RES:256DMPC) Temperature: 323K ~35-49 SPC/lipid

Res11/DMPC bilayers (no micelle formation) Simulation time: 340 ns 0 ns 10 ns 200 ns 280 ns 300 ns

Res19/DMPC (micelle formation) Severe membrane disruption Res19/DMPC (micelle formation) Severe membrane disruption Simulation time: 175 ns

Res25/DMPC (micele bilayer interaction) Formation of gel phase domain Res25/DMPC (micele bilayer interaction) Formation of gel phase domain Simulation time: 90 ns

Steps in the pore-forming process of the incorporation

Summary  Alternative mechanisms of incorporation lead to marked differences in disruption.  Alternative final phases depending on chain length: a) lamellar - RES11, b) hexagonal - RES19, c) lamellar with gel phase domain - RES25  Final bilayers asymmetric: much longer simulation times required for equilibration  Alternative mechanisms of incorporation lead to marked differences in disruption.  Alternative final phases depending on chain length: a) lamellar - RES11, b) hexagonal - RES19, c) lamellar with gel phase domain - RES25  Final bilayers asymmetric: much longer simulation times required for equilibration