Binding of Cytotoxic Aβ25–35 Peptide to the Dimyristoylphosphatidylcholine Lipid Bilayer

Aβ25–35 is a short, cytotoxic, and naturally occurring fragment of the Alzheimer’s Aβ peptide. To map the molecular mechanism of Aβ25–35 binding to the zwitterionic dimyristoylphosphatidylcholine (DMPC) bilayer, we have performed replica exchange with solute tempering molecular dynamics simulations using all-atom explicit membrane and water models. Consequences of sequence truncation on the binding mechanism have been measured by utilizing as a control our previous simulations probing binding of the longer peptide Aβ10–40 to the same bilayer. The most intriguing feature of Aβ25–35 binding to the DMPC bilayer is a coexistence of two bound states with strikingly different characteristics: a dominant surface-bound state and a less stable inserted state. In the surface-bound state, the peptide samples extended conformations, in which its unbound C-terminal is pointed away from the bilayer. In contrast, in the inserted state, the C-terminal resides deep in the bilayer hydrophobic core. In both states, the N-terminal remains anchored to the bilayer. Free energy landscape analysis reveals that the two states are separated by a moderate barrier, suggesting that Aβ25–35 monomer may frequently interconvert between them. The net effect of Aβ25–35 binding is a minor impact on the bilayer structure, which contrasts with the considerable bilayer perturbations induced by a longer Aβ10–40 peptide penetrating deep into the bilayer core. Therefore, we conclude that the binding mechanisms of Aβ25–35 and Aβ10–40 peptides are different. Potential implications of our results for Aβ25–35 cytotoxicity are discussed. A comparison of experimental data with our findings reveals a good agreement.