Template Induced Conformational Change of Amyloid-β Monomer Wenhui Xi, Wenfei Li,* and Wei Wang* National Laboratory of Solid State Microstructure, and Department of Physics, Nanjing University, Nanjing 210093, China * S Supporting Information ABSTRACT: Population of aggregation-prone conformers for the monomeric amyloid-β (Aβ) can dramatically speed up its fibrillar aggregation. In this work, we study the effect of preformed template on the conformational distributions of the monomeric Aβ by replica exchange molecular dynamics. Our results show that the template consisting of Aβ peptides with cross-β structure can induce the formation of β-rich conformations for the monomeric Aβ, which is the key feature of the aggregation-prone conformers. Similar effect is observed when the hIAPP peptides and poly alanine peptides were used as templates, suggesting that the template effect is insensitive to the sequence details of the template peptides. In comparison, the template with helical structure has no significant effects on the β-propensity of the monomeric Aβ. Analysis to the interaction details revealed that the template tends to disrupt the intrapeptide interactions of the monomeric Aβ, which are absent in the fibrillar state, suggesting that the preformed template can reorganize the intrapeptide interactions of the monomeric Aβ during the capturing stage and reduce the energy frustrations for the fibrillar aggregations. ■ INTRODUCTION Accumulation of amyloid-β (Aβ) aggregates in the brain is the key pathological feature of the Alzheimer’s disease (AD). 1-5 It was widely accepted that the aggregation of the Aβ peptides is involved in the AD pathogenesis. 6,7 Experimental data showed that the structure of the Aβ peptide in the aggregates are dominated by parallel cross-β. 8-11 However, in aqueous solvent, the Aβ is mostly unstructured. Therefore, during the aggregation of the Aβ peptides, the monomer undergoes conformational conversion from random structure to β-strands. In addition, a number of theoretical and experimental works showed that the preformation of the aggregation-prone conformers of the monomeric Aβ peptides, which are rich of β-strands, can significantly speed up the further elongation of the fibrils. 12-19 Undoubtedly, revealing the molecular mecha- nism of the conformational change of the monomeric Aβ during the aggregation is crucial to understanding the pathology of the AD disease. Particularly, it is interesting to investigate which factors can promote the formation of the aggregation-prone conformer and therefore speed up the fibrillar aggregations. It was shown that many physical and chemical factors, including pH environment, 20,21 temperature, 22,23 organic solvent, 24-27 mutation, 28 and metal ions 13,29-31 etc., can affect the conformational distribution of the Aβ monomer and enhance the aggregation-prone conformations. For example, in ref 21, using molecular dynamics simulations, Brooks and co- workers observed that modestly acidic pH environment increases the population of the β-turn conformations of the monomeric Aβ, which can further contribute to the fibrillar aggregations. In our previous work, we revealed that binding of divalent metal ions to the N-terminal part of the Aβ monomer promotes the formation of the aggregation-prone conforma- tions. 13 Such works can be highly useful to the understanding of the Aβ aggregation in the cell environment in which Aβ peptides encounter extremely complicated physical and chemical factors. Recently, a number of works have been devoted to revealing the growth mechanism of the Aβ fibrils. 12,32-41 Particularly, a two-step dock-and-lock mechanism was proposed to interpret the elongation kinetics of the Aβ fibrils. 15 In this mechanism, the disordered Aβ monomer first docks with the fibril end through diffusion-limited kinetics. Then, the Aβ monomer is locked to the fibril by conformational reorganization and forms the correct cross-β structure. Detailed characterizations to the thermodynamics of the above-mentioned docking and locking transitions were reported by Takeda and Klimov in ref 32 and by Han and Hansmann in ref 33 using atomistic molecular dynamics simulations. Although, the monomeric Aβ fully folds to the cross-β structure only after its locking to the growing fibril, it senses the interactions arising from the template peptides during its approaching to the fibril template. Such interactions will no doubt modulate the conformational distribution of the monomeric Aβ before its final locking to the fibril. It is interesting to investigate whether such conformational modulations by the template peptides can promote the formation of the above-mentioned aggregation- prone conformations. In this work, by using replica exchange molecular dynamics (REMD), we study the effects of the preformed template on the structure of the approaching Aβ monomer. We are interested in the following questions: (i) how the template Received: January 12, 2012 Revised: May 3, 2012 Published: June 6, 2012 Article pubs.acs.org/JPCB © 2012 American Chemical Society 7398 dx.doi.org/10.1021/jp300389g | J. Phys. Chem. B 2012, 116, 7398-7405