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Amyloid beta-protein monomer folding: free-energy surfaces reveal alloform-specific differences.

ABSTRACT: Alloform-specific differences in structural dynamics between amyloid beta-protein (Abeta) 40 and Abeta42 appear to underlie the pathogenesis of Alzheimer's disease. To elucidate these differences, we performed microsecond timescale replica-exchange molecular dynamics simulations to sample the conformational space of the Abeta monomer and constructed its free-energy surface. We find that neither peptide monomer is unstructured, but rather that each may be described as a unique statistical coil in which five relatively independent folding units exist, comprising residues 1-5, 10-13, 17-22, 28-37, and 39-42, which are connected by four turn structures. The free-energy surfaces of both peptides are characterized by two large basins, comprising conformers with either substantial alpha-helix or beta-sheet content. Conformational transitions within and between these basins are rapid. The two additional hydrophobic residues at the Abeta42 C-terminus, Ile41 and Ala42, significantly increase contacts within the C-terminus, and between the C-terminus and the central hydrophobic cluster (Leu17-Ala21). As a result, the beta-structure of Abeta42 is more stable than that of Abeta40, and the conformational equilibrium in Abeta42 shifts towards beta-structure. These results suggest that drugs stabilizing alpha-helical Abeta conformers (or destabilizing the beta-sheet state) would block formation of neurotoxic oligomers. The atomic-resolution conformer structures determined in our simulations may serve as useful targets for this purpose. The conformers also provide starting points for simulations of Abeta oligomerization-a process postulated to be the key pathogenetic event in Alzheimer's disease.

SUBMITTER: Yang M

PROVIDER: S-EPMC2673916 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Amyloid beta-protein monomer folding: free-energy surfaces reveal alloform-specific differences.

Yang Mingfeng M Teplow David B DB

Journal of molecular biology 20080924 2

Alloform-specific differences in structural dynamics between amyloid beta-protein (Abeta) 40 and Abeta42 appear to underlie the pathogenesis of Alzheimer's disease. To elucidate these differences, we performed microsecond timescale replica-exchange molecular dynamics simulations to sample the conformational space of the Abeta monomer and constructed its free-energy surface. We find that neither peptide monomer is unstructured, but rather that each may be described as a unique statistical coil in ...[more]

PMID: 18835397

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Project description:Familial Alzheimer's disease (FAD) mutations of the amyloid β-peptide (Aβ) are known to lead to early onset and more aggressive Alzheimer's disease. FAD mutations such as "Iowa" (D23N), "Arctic" (E22G), "Italian" (E22K), and "Dutch" (E22Q) have been shown to accelerate Aβ aggregation relative to the wild-type (WT). The mechanism by which these mutations facilitate increased aggregation is unknown, but each mutation results in a change in the net charge of the peptide. Previous studies have used nonpolarizable force fields to study Aβ, providing some insight into how this protein unfolds. However, nonpolarizable force fields have fixed charges that lack the ability to redistribute in response to changes in local electric fields. Here, we performed polarizable molecular dynamics simulations on the full-length Aβ42 of WT and FAD mutations and calculated folding free energies of the Aβ15-27 fragment via umbrella sampling. By studying both the full-length Aβ42 and a fragment containing mutations and the central hydrophobic cluster (residues 17-21), we were able to systematically study how these FAD mutations impact secondary and tertiary structure and the thermodynamics of folding. Electrostatic interactions, including those between permanent and induced dipoles, affected side-chain properties, salt bridges, and solvent interactions. The FAD mutations resulted in shifts in the electronic structure and solvent accessibility at the central hydrophobic cluster and the hydrophobic C-terminal region. Using umbrella sampling, we found that the folding of the WT and E22 mutants is enthalpically driven, whereas the D23N mutant is entropically driven, arising from a different unfolding pathway and peptide-bond dipole response. Together, the unbiased, full-length, and umbrella sampling simulations of fragments reveal that the FAD mutations perturb nearby residues and others in hydrophobic regions to potentially alter solubility. These results highlight the role electronic polarizability plays in amyloid misfolding and the role of heterogeneous microenvironments that arise as conformational change takes place.

Dataset Information

Amyloid beta-protein monomer folding: free-energy surfaces reveal alloform-specific differences.

Publications

Amyloid beta-protein monomer folding: free-energy surfaces reveal alloform-specific differences.

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