Effects of Solvent on the Structure of the Alzheimer Amyloid-β(25–35) Peptide

Abstract

The free energy landscape for folding of the Alzheimer's amyloid-beta(25-35) peptide is explored using replica exchange molecular dynamics in both pure water and in HFIP/water cosolvent. This amphiphilic peptide is a natural by-product of the Alzheimer's amyloid-beta(1-40) peptide and retains the toxicity of its full-length counterpart as well as the ability to aggregate into beta-sheet-rich fibrils. Our simulations reveal that the peptide preferentially populates a helical structure in apolar organic solvent, while in pure water, the peptide adopts collapsed coil conformations and to a lesser extent beta-hairpin conformations. The beta-hairpin is characterized by a type II' beta-turn involving residues G29 and A30 and two short beta-strands involving residues N27, K28, I31, and I32. The hairpin is stabilized by backbone hydrogen-bonding interactions between residues K28 and I31; S26 and G33; and by side-chain-to-side-chain interactions between N27 and I32. Implications regarding the mechanism of aggregation of this peptide into fibrils and the role of the environment in modulating secondary structure are discussed.

Hydrophobic interactions in the formation of secondary structures in small peptides

“…The first sequence (GSNKGAIIGLM) we studied corresponds to residues 25-35 of amyloid-β which is found in patients with Alzheimer's disease [23,[56][57][58]. The second sequence (KHMAGAAAAGA) corresponds to residues 110-120 of the amyloidogenic β-hairpin peptide of the Syrian hamster prion protein, H1 peptide [23].…”

“…[59,60] implicated in Parkinson's disease. Explicit solvent simulations and experiments have shown that these sequences assume a large amount of β and coiled conformations in aqueous environments whereas the α helix is their dominant conformational pattern in solvents that mimic the interior of membranes (e.g., hexafluoroisopropanol-water mixture) [23,24,56]. Figure 10 shows how R cutoff affects secondary structure content.…”

Computational Simulations of the Early Steps of Protein Aggregation

“…Another severe limitation of REMD is that the number of replicas increases rapidly with the size of the system, limiting its applicability to small all-atom systems in solvent such as the monomer of full-length Ab, and dimers and trimers of short fragments. [45][46][47][48] The use of implicit solvent and coarse-grained models lifts some of the limitations of both MD and REMD on two counts. First, by removing some of the dampening due to the collision with the solvent, they accelerate the sampling of the phase space by as much as two orders of magnitude.…”

Molecular Dynamics Simulations to Clarify the Concentration Dependency of Protein Aggregation

“…Aβ 25−35 is a peptide fragment that has been studied widely in both experiments [4][5][6][7][8][9] and simulations [10,11]. In the experiments, it has been shown that this fragment aggregates into β-structures [4][5][6].…”