Distinct Dimerization for Various Alloforms of the Amyloid-Beta Protein: Aβ 1-40 ,Aβ 1-42 , and Aβ 1-40 (D23N) Se ́ bastien Côte ́ , † Rozita Laghaei, † Philippe Derreumaux, ‡ and Normand Mousseau* ,† † De ́ partement de Physique and Groupe de recherche sur les prote ́ ines membranaires (GEPROM), Universite ́ de Montre ́ al, C.P. 6128, succursale Centre-ville, Montre ́ al (Que ́ bec), Canada ‡ Laboratoire de Biochimie The ́ orique, UPR 9080 CNRS, Institut de Biologie Physico-Chimique, Universite Paris Diderot, Paris 7 and Institut Universitaire de France, 13 rue Pierre et Marie Curie, 75005 Paris, France * S Supporting Information ABSTRACT: The Amyloid-beta protein is related to Alzheimer’s disease, and various experiments have shown that oligomers as small as the dimer are cytotoxic. Two alloforms are mainly produced: Aβ 1-40 and Aβ 1-42 . They have very different oligomer distributions, and it was recently suggested, from experimental studies, that this variation may originate from structural differences in their dimer structures. Little structural information is available on the Aβ dimer, however, and to complement experimental observations, we simulated the folding of the wild-type Aβ 1-40 and Aβ 1-42 dimers as well as the mutated Aβ 1-40 (D23N) dimer using an accurate coarse-grained force field coupled to Hamiltonian-temperature replica exchange molecular dynamics. The D23N variant impedes the salt-bridge formation between D23 and K28 seen in the wild-type Aβ, leading to very different fibrillation properties and final amyloid fibrils. Our results show that the Aβ 1-42 dimer has a higher propensity than the Aβ 1-40 dimer to form β-strands at the central hydrophobic core (residues 17-21) and at the C-terminal (residues 30-42), which are two segments crucial to the oligomerization of Aβ. The free energy landscape of the Aβ 1-42 dimer is also broader and more complex than that of the Aβ 1-40 dimer. Interestingly, D23N also impacts the free energy landscape by increasing the population of configurations with higher β-strand propensities when compared against Aβ 40 . In addition, while Aβ 1-40 (D23N) displays a higher β-strand propensity at the C-terminal, its solvent accessibility does not change with respect to the wild-type sequence. Overall, our results show the strong impact of the two amino acids Ile41-Ala42 and the salt-bridge D23-K28 on the folding of the Aβ dimer. ■ INTRODUCTION The hallmark feature of many neurodegenerative diseases such as Parkinson, Huntington, Creutzfeld-Jakob, and Alzheimer is the appearance of β-sheet-rich insoluble filamentous deposits in brain tissues. 1,2 Alzheimer’s disease, for instance, is charac- terized by the formation of extra- and intracellular deposits respectively composed of the amyloid β and τ proteins. The amyloid β (Aβ) protein, whose aggregation and oligomer deposition are correlated with the degradation of brain tissues, 3 exists in many different alloforms that are produced through the cleavage of the amyloid precursor protein (APP). Aβ 1-40 and Aβ 1-42 are the most abundant in neuritic amyloid plaques, 4 and the presence of two hydrophobic residues, Ile41 and Ala42, at the C-terminal leads to very distinct oligomer distributions 5-7 during fibrillation 8-10 in vitro. While the exact neurotoxic mechanisms for oligomers are still a matter of debate, 11 considerable experimental evidence collected over the past decade shows that metastable Aβ soluble oligomers correlate more with increased neurotoxicity. 12 While the exact size of these oligomers is not completely clear, even the dimer was recently observed to be synaptotoxic. 13 Both the growth kinetics and toxicity are strongly affected by the exact amino sequence of Aβ peptides. Higher Aβ 1-42 /Aβ 1-40 ratio increases toxicity. 14 Aβ 1-40 and Aβ 1-42 also show distinct distributions of low order oligomers, which could be due to differences in their dimer equilibrium structures. 15 Mutations can also affect oligomeric growth and the final product. The Iowa familial mutation, Aβ 1-40 (D23N), for example, fibrillates into antiparallel β-sheet fibril morphologies without any lag phase, 16,17 contrary to what is observed with both Aβ 1-40 and Aβ 1-42 , which show a lag phase and parallel organization. 9,10 Characterizing the Aβ dimerization at the molecular level is crucial for understanding the origin of the various aggregation properties for these different alloforms. 5-10 To date, very little experimental information is available for the dimer because it is aggregation-prone and exists in equilibrium with fibrils, monomers, and higher-order oligomers. 6,8 Recently, a combined study using photoinduced cross-linking and circular dichroism (CD) on Aβ 1-40 showed that the dimerization increases the β-strand propensity and toxicity as compared with the monomer. 18 In the absence of high-resolution structure data such as solution NMR, however, only computer simulations can provide access to detailed structural and kinetic information about the formation of dimers. Until now, the folding of full-length Aβ Received: December 31, 2011 Revised: March 9, 2012 Published: March 12, 2012 Article pubs.acs.org/JPCB © 2012 American Chemical Society 4043 dx.doi.org/10.1021/jp2126366 | J. Phys. Chem. B 2012, 116, 4043-4055