@article {2016|1712,
	title = {Dimerization Mechanism of Alzheimer A beta(40) Peptides: The High Content of Intrapeptide-Stabilized Conformations in A2V and A2T Heterozygous Dimers Retards Amyloid Fibril Formation},
	journal = {J. Phys. Chem. B},
	volume = {120},
	number = {47},
	year = {2016},
	pages = {12111{\textendash}12126},
	abstract = {Amyloid beta (A beta) oligomerization is associated with the origin and progression of Alzheimer{\textquoteright}s disease (AD). While the A2V mutation enhances aggregation kinetics and toxicity, mixtures of wild-type (WT) and A2V, and also WT and A2T, peptides retard fibril formation and protect against AD. In this study, we simulate the equilibrium ensemble of WT:A2T A beta(40) dimer by means of extensive atomistic replica exchange molecular dynamics and compare our results with previous equivalent simulations of A2V:A2V, WT:WT, and WT:A2V A beta(40) dimers for a total time scale of nearly 0.1 ms. Qualitative comparison of the resulting thermodynamic properties, such as the relative binding free energies, with the reported experimental kinetic and thermodynamic data affords us important insight into the conversion from slow-pathway to fast-pathway dimer conformations. The crucial reaction coordinate or driving force of such transformation turns out to be related to hydrophobic interpeptide interactions. Analysis of the equilibrium ensembles shows that the fast-pathway conformations contain interpeptide out-of-register antiparallel beta-sheet structures at short interpeptide distances. In contrast, the slow-pathway conformations are formed by the association of peptides at large interpeptide distances and high intrapeptide compactness, such as conformations containing intramolecular three-stranded beta-sheets which sharply distinguish fast (A2V:A2V and WT:WT) and slow (WT:A2T and WT:A2V) amyloid-forming sequences. Also, this analysis leads us to predict that a molecule stabilizing the intramolecular three-stranded beta-sheet or inhibiting the formation of an interpeptide beta-sheet spanning residues 17-20 and 31-37 would further reduce fibril formation and probably the cytotoxicity of A beta species.},
	issn = {1520-6106},
	doi = {10.1021/acs.jpcp.6b10722},
	author = {Phuong Hoang Nguyen and Fabio Sterpone and Pouplana, Ramon and Philippe Derreumaux and Campanera, Josep M.}
}
@article {2016|1578,
	title = {Impact of the A2V Mutation on the Heterozygous and Homozygous A beta 1-40 Dimer Structures from Atomistic Simulations},
	journal = {Acs Chem. Neurosci.},
	volume = {7},
	number = {6},
	year = {2016},
	month = {jun},
	pages = {823{\textendash}832},
	abstract = {The A2V mutation was reported to protect from Alzheimer{\textquoteright}s disease in its heterozygous form and cause an early Alzheimer{\textquoteright}s disease type dementia in its homozygous form. Experiments showed that the aggregation rate follows the order A2V > WT (wild-type) > A2V-WT. To understand the impact of this mutation, we carried out replica exchange molecular dynamics simulations of A beta 1-40 WT-A2V and A2V-A2V dimers and compared to the WT dimer. Our atomistic simulations reveal that the mean secondary structure remains constant, but there are substantial differences in the intramolecular and intermolecular conformations upon single and double A2V mutation. Upon single mutation, the intrinsic disorder is reduced, the intermolecular potential energies are reduced, the population of intramolecular three-stranded beta-sheets is increased, and the number of all a dimer topologies is decreased. Taken together, these results offer an explanation for the reduced aggregation rate of the A beta 1-40 A2V-WT peptides and the protective effect of A2V in heterozygotes.},
	issn = {1948-7193},
	doi = {10.1021/acschemneuro.6b00053},
	author = {Phuong Hoang Nguyen and Fabio Sterpone and Campanera, Josep M. and Nasica-Labouze, Jessica and Philippe Derreumaux}
}
