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Physical Chemistry Chemical Physics


Inclusion of lipopeptides into the DMPC lipid bilayer prevents Aβ peptide insertion


Authors: Niyati Parikh; Dmitri Klimov

Publication Date: -0001-11-30  Article ASAP

Using all-atom explicit water model and replica exchange with solute tempering molecular dynamics we have studied the binding of Abeta10-40 peptide to the mixed cationic bilayer composed of DMPC lipids and C14-KAAK lipopeptides (LP). Using as a control our previous replica exchange simulations probing binding of the same peptide to the zwitterionic DMPC bilayer we assessed the impact of lipopeptides on Abeta binding mechanism. We found that binding to the mixed DMPC+LP bilayer does not enhance Abeta helix propensity as much as binding to the pure DMPC bilayer. Tertiary interactions also differ in the peptide bound to the DMPC+LP bilayer due to reduced helix content, salt bridge disruption, and formation of new long-range hydrophobic interactions. More importantly, we showed that mixing lipopeptides into the DMPC bilayer prevents Abeta10-40 insertion forcing the peptide to reside on the bilayer surface and considerably destabilizes Abeta-bilayer interactions leading to formation of a shallow water layer between the peptide and the bilayer. Furthermore, we demonstrated that Abeta10-40 peptide causes minor DMPC+LP bilayer thinning and perturbation beneath its binding footprint. These observations stand in sharp contrast to Abeta10-40 binding to the pure DMPC bilayer, which results in deep peptide insertion and significant disruption of the bilayer structure. We argued that lipopeptides expel Abeta10-40 peptide from the bilayer due to strong, mostly electrostatic, interfacial interactions introduced by the lipopeptides into the bilayer. We therefore propose that C14-KAAK lipopeptides can be used to engineer lipid bilayers, which withstand binding of Alzheimer's Abeta peptides.  Read more