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To address whether bilayer composition influences the oligomeric state of AH2, we have undertaken a series of cross-linking experiments, with AH2 in the presence of neutral lipid vesicles composed of POPC and negatively charged lipid vesicles composed of POPC and POPG (Fig.?5). In the absence of the membrane permeable amine cross-linker DSS, AH2 runs as a monomeric species on the denaturing SDS-PAGE gel, close to its predicted molecular weight of 2965?Da. In neutral bilayers composed of POPC, the presence of the cross-linker results in the formation of a ��ladder��, indicating the presence of higher oligomeric species within the bilayer, with hexameric complexes readily observable. In contrast, in the presence of negatively charged lipids the degree of http://www.selleckchem.com/products/gsk2126458.html cross-linking is significantly curtailed with a trimeric complex being the largest readily observed. In all simulations containing anionic lipids, the AH2 peptides were observed to diffuse from the bulk water towards the bilayer such that they formed surface-interactions https://en.wikipedia.org/wiki/GBA3 with the model membrane. We did not observe peptide insertion into the hydrophobic core region of the lipid bilayer in any of our simulations. A typical scenario is described below for a system containing 10? peptides with the bilayer composed of a 3:1 ratio of POPC:POPG phospholipids. After only 3?ns of simulation, a single peptide became associated with the surface of the membrane. It quickly adopted an orientation parallel to the plane of the membrane. Higher oligomers, a tetramer, trimer and dimer begin to form in solution after?~?4?ns with the tetramer becoming surface-associated to the membrane by?~?7?ns. After?~?22?ns, the dimer is also surface-associated and aggregates with the already surface-associated tetramer forming a hexameric structure (Fig.?6A). During this time, the trimer becomes surface-associated with the other leaflet of the lipid bilayer. Thus none of the peptides remain detached from the membrane after about ~?22?ns. Interestingly, the aggregates do not appear to be ordered in anyway, with the peptides arranging in random orientations. Analysis of lipid-protein interactions (where interaction is defined as r?��?6??) revealed a marked preference for PG lipids over PC lipids (Fig.?6B). For example when all ten peptides are surface associated, there are?~?450�C500 lipid�Cprotein contacts (counting all the lipid and protein particles) with PG lipids but only?~?400�C420 with PC lipids, despite there being a 3:1 excess of the latter. When only two peptides are surface associated then, the number of contacts is ~?50 for PG lipids and