The Influence of Fatty Acids on the GpA Dimer Interface by Coarse-Grained Molecular Dynamics Simulation

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.

Dynamics of the Glycophorin A Dimer in Membranes of Native-Like Composition Uncovered by Coarse-Grained Molecular Dynamics Simulations

“…The model protein GpA prefers areas, which are enriched in lipids with unsaturated fatty acids, indicating that in general proteins without lipid anchor are sorted into these domains in the plasma membrane. Together with our previous results on the influence of different fatty acids on dimer formation [ 40 ] we conclude that fatty acids and the presence of cholesterol are the major determinants that influence protein interaction (and most likely function) in native membranes without having a direct catalytic or structural role for the corresponding protein. In model membranes a huge amount of protein can induce domain formation [ 54 ], whether this is the case in native membranes needs to be investigated in future.…”

“…The adopted GpA dimer interfaces in the native-like membrane are most comparable to the interfaces of the nFA+CHOL membrane ( Fig 2B ; correlation: 0.80). Furthermore, the adopted interfaces are similar for both membranes missing cholesterol (nFA+head and nFA; Fig 2B ; correlation: 0.95) and the most frequent interface (cluster 9) is also one of the most frequent interfaces in the self-assembly simulations in pure PC model membranes, which also lack cholesterol ([ 40 ], S3 Fig ). These results indicate that cholesterol has a major impact on the preferred interface of the protein.…”

“…Both interfaces occupy different sides of the helix and have different key resides which form the interface ( Fig 2C ). The interface of cluster 40 was observed with very low frequency in self-assembly simulations of 10 μs length in pure PC model membranes this interface ([ 40 ], S3 Fig ). This prompted the question whether head groups or cholesterol have a major impact on interface structure and stability.…”

“…The analysis of visited interfaces of the GpA dimer was performed as described [ 40 ], in short: For each frame a contact map was constructed saving the occurring residue contacts. Based on these contact maps a distance matrix, using the Dice dissimilarity, was calculated to perform a clustering and to group the same interfaces.…”

The role of hydrophobic matching on transmembrane helix packing in cells

“…The above view based on experimental work is supported by molecular simulations of model systems, where GpA has served as a centerpiece. Hence, Molecular Dynamics (MD) simulations on GpA have been employed to investigate phenomena such as membrane insertion 22, dimer structure 2324, and dimerization energetics 25.…”