Structure of the Amyloid-β (1−42) Monomer Absorbed To Model Phospholipid Bilayers: A Molecular Dynamics Study

Abstract

The amyloid-beta (Abeta) peptide, the 39 to 43 amino acid peptide that plays a substantial role in Alzheimer's disease, has been shown to interact strongly with lipids both in vitro and in vivo. Abeta-lipid interactions have been proposed as a considerable factor in accelerating Abeta aggregation through the templating role of membranes in aggregation disorders. Previous work has shown that anionic lipids are able to significantly increase Abeta aggregation rate and induce a structural conversion in Abeta from a random coil to a beta-structure that is similar to the monomer structure observed in mature fibrils. However, it is unclear if this structural change occurs with the Abeta monomer because of direct interactions with the lipids or if the structural change results from protein-protein interactions during oligomerization. We use extensive replica exchange molecular dynamics simulations of an Abeta monomer bound to a homogeneous model zwitterionic or anionic lipid bilayer. From these simulations, we do not observe any significant beta-structure formation except for a small, unstable beta-hairpin formed on the anionic dioleylphosphatidylserine bilayer. Further, we see that the Asp23-Lys28 salt bridge that plays a role in beta-hairpin formation is not substantially formed on the bilayer surface and that Lys28 preferentially interacts with lipids when bound to the bilayer. These results suggest that the structural conversion seen in experiments are not due to the ordering of monomeric Abeta on the bilayer surface but are a result of protein-protein interactions enhanced by Abeta binding to the cell membrane.

Scaling and alpha-helix regulation of protein relaxation in a lipid bilayer

“…Simulations addressing inserted Aß as the initial state show a wide range of behavior from anchoring to the extracellular membrane interface, 24,27,28 to ejection from the membrane. 26,31 However, few simulations 26 have addressed Aß interactions with membranes composed of CHOL and unsaturated lipids.…”

“…[24][25][26][27][28][29] Simulation of aggregation and release processes 26,30,31 are particularly relevant to the work presented here because they can compete with unfolding, penetration, and binding phenomena.…”

Lipid composition influences the release of Alzheimer's amyloid β‐peptide from membranes

“…All previous MD studies of Ab in membranes 17,18,27,36,[39][40][41] have consisted of only a single lipid type or an implicit model representing a membrane. In this work, however, we have explored numerous explicit model membranes, including the most complex lipid environments in which Ab has been simulated to date, rafts that correspond very closely to the lipid matrix that Ab encounters upon its production following c-secretase cleavage of APP.…”

Cholesterol Promotes the Interaction of Alzheimer β-Amyloid Monomer with Lipid Bilayer

“…Davis et al have reported that Aβ 1-42 monomer with initial α-helical or β-hairpin structure unfolds into random coils and turns on the zwitterionic DPPC bilayer while remaining in its initial α-helical or β-hairpin structure on the anionic DOPS bilayer. 39,40 In addition to the study of Aβ bound to the membrane surface, Lemkul et al 41,43 (GROMACS96 with an explicit membrane), Miyashita et al 44 (CHARMM22 with implicit GBSW membrane and replica-exchange MD), and Strodel et al 42 (CHARMM19 with implicit IMM1 membrane and the Basin-hopping method) have used different computational approaches and force fields to study the conformation of Aβ 1-40/42 monomer inserted in the membrane. Lemkul et al found that the N-terminal residues of 1-24/1-28 retain its α-helical conformation within the DPPC bilayer, but the C-terminal residues of 25-42/29-42 adopt a disordered structure on the DPPC surface.…”