Alzheimer's Aß10-40 Peptide Binds and Penetrates DMPC Bilayer: An Isobaric-Isothermal Replica Exchange Molecular Dynamics Study.

The journal of physical chemistry. B

PubMedID: 24547901

Lockhart C, Klimov DK. Alzheimer's Aß10-40 Peptide Binds and Penetrates DMPC Bilayer: An Isobaric-Isothermal Replica Exchange Molecular Dynamics Study. J Phys Chem B. 2014;.
Using all-atom explicit solvent model and isobaric-isothermal replica exchange molecular dynamics we studied binding of Abeta10-40 monomers to zwitterionic DMPC bilayer. Our simulations suggest three main conclusions. First, binding of Abeta10-40 monomer to the DMPC bilayer causes dramatic structural transition in the peptide resulting in the formation of stable helical structure in the C-terminal. In addition, binding to the lipid bilayer induces the formation of intrapeptide Asp23-Lys28 salt bridge. We argue that the emergence of helix is the consequence of hidden helix propensity harbored in the Abeta10-40 C-terminal. This propensity is revealed by the lipids cross-bridging amino acids in helical conformations and by significant hydrophobic moment of the C-terminal. Second, the central hydrophobic cluster and, particularly, the C-terminal of Abeta10-40 not only govern binding to the bilayer, but also penetrate into bilayer core. In contrast, the polar N-terminal and turn region form interactions mainly with the bilayer surface. Third, our simulations suggest that upon Abeta10-40 binding to the bilayer a highly heterogeneous local environment emerges along Abeta10-40 chain. The N-terminal is exposed to polar well hydrated medium, whereas the C-terminal is largely shielded from water residing in mostly hydrophobic environment. The implication of our results is that Abeta aggregation mediated by zwitterionic lipid bilayer is likely to be different from that in bulk water.