Abstract
The hydrophobic thickness of membranes, which is manly defined by fatty acids, influences the packing of transmembrane domains of proteins and thus can modulate the activity of these proteins. We analyzed the dynamics of the dimerization of Glycophorin A (GpA) by molecular dynamics simulations to describe the fatty acid dependence of the transmembrane region assembly. GpA represents a well-established model for dimerization of single transmembrane helices containing a GxxxG motif in vitro and in silico. We performed simulations of the dynamics of the NMR-derived dimer as well as self-assembly simulations of monomers in membranes composed of different fatty acid chains and monitored the formed interfaces and their transitions. The observed dimeric interfaces, which also include the one known from NMR, are highly dynamic and converted into each other. The frequency of interface formation and the preferred transitions between interfaces similar to the interface observed by NMR analysis strongly depend on the fatty acid used to build the membrane. Molecular dynamic simulations after adaptation of the helix topology parameters to better represent NMR derived structures of single transmembrane helices yielded an enhanced occurrence of the interface determined by NMR in molecular dynamics simulations. Taken together we give insights into the influence of fatty acids and helix conformation on the dynamics of the transmembrane domain of GpA.
Highlights
All living cells are surrounded by membranes, which are mainly composed of glycerophospholipids, sphingolipids and sterols [1,2], which consist of a hydrophilic head group and a hydrophobic tail.The lipids are arranged in two layers within the membrane, with the tails packed against each other
By molecular dynamics (MD) simulations it has been shown that PC lipids with saturated and unsaturated fatty acid chains separate spontaneously into an liquid ordered phase, containing the saturated lipids and cholesterol, and an liquid disordered phase, containing the lipids with unsaturated fatty acids [4,5]
Phase separation and compartmentalization are present in biological membranes, for example lipid rafts are observed in the eukaryotic plasma membrane, which are enriched in sphingolipids and cholesterol [7]
Summary
All living cells are surrounded by membranes, which are mainly composed of glycerophospholipids, sphingolipids and sterols [1,2], which consist of a hydrophilic head group and a hydrophobic tail. The lipids are arranged in two layers within the membrane, with the tails packed against each other. Glycerophospholipids are the most prominent components of biological membranes and phosphatidylcholine (PC) is the most frequently occurring lipid in biological systems [3]. A small mismatch between the saturated and unsaturated fatty acids reduces the driving force for segregation, while the increase of cholesterol leads to an enhanced driving force for the phase separation [6]. Phase separation and compartmentalization are present in biological membranes, for example lipid rafts are observed in the eukaryotic plasma membrane, which are enriched in sphingolipids and cholesterol [7]
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