Do cholesterol and sphingomyelin change the mechanism of Aβ25-35 peptide binding to zwitterionic bilayer?

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Abstract

Using replica exchange with solute tempering all-atom molecular dynamics we studied the equilibrium binding of Abeta25-35 peptide to the ternary bilayer composed of an equimolar mixture of dimyristoylphosphatidylcholine (DMPC), N-palmitoylsphingomyelin (PSM), and cholesterol. Binding of the same peptide to the pure DMPC bilayer served as a control. Due to significant C-terminal hydrophobic moment, binding to the ternary and DMPC bilayers promotes helical structure in the peptide. For both bilayers a polarized binding profile is observed, in which the N-terminus anchors to the bilayer surface, whereas the C-terminus alternates between unbound and inserted states. Both ternary and DMPC bilayers feature two Abeta25-35 bound states, surface bound S and inserted I, separated by modest free energy barriers. Experimental data are in agreement with our results, but indicate that cholesterol impact is Abeta fragment dependent. For Abeta25-35 we predict that its binding mechanism is independent of the inclusion of PSM and cholesterol into the bilayer.