Replica exchange molecular dynamics study of the amyloid beta (11–40) trimer penetrating a membrane†
Alzheimer's disease is characterized by the interaction of neurotoxic Aβ oligomers with cellular membranes, which disturbs ion homeostasis. To determine the putative structures of the transmembrane 3Aβ11–40 oligomer, temperature replica exchange molecular dynamics (REMD) simulations with an explicit solvent have been employed to monitor the structural changes when interaction of the oligomer with the membrane DPPC lipid bilayer is induced. Although the initial conformation of the 3Aβ11–40 transmembrane was fibril-like, the obtained results are in good agreement with previous experiments, in which the β-structure of the Aβ oligomer represents ∼40% of the structure in the average of all considered snapshots. The statistical coil structure, which is located near and interacts with the membrane headgroups, amounts to almost 60% of the structure. The transmembrane Aβ oligomer helix structure basically disappears during the REMD simulations. Instead of the Asp23–Lys28 salt bridge, the polar contact between Asp23 and Asn27 has been found to be a factor stabilizing the structure of the Aβ oligomer. Although numerous polar contacts between lipid headgroups and the peptide have been found, free energy perturbation calculations indicated that van der Waals interactions are the key factor determining the binding between the Aβ trimer and the membrane. It may be argued that the Aβ11–40 trimer can be easily inserted into the membrane because the binding free energy between the trimer and the membrane reaches −70 kcal mol−1. The collision cross section of the optimized structures of 1341 ± 23 Å2 agrees well with the experimental values for the solvated Aβ trimer.