title: Varied Probability of Staying Collapsed/Extended at the Conformational Equilibrium of Monomeric Aβ40 and Aβ42.
abstract: In present study, we set out to investigate the conformation dynamics of Aβ40 and Aβ42 through exploring the impact of intra-molecular interactions on conformation dynamics using equilibrium molecular dynamics simulations. Our 40 microsecond-scale simulations reveal heterogeneous conformation ensembles of Aβ40 and Aβ42 that encompass ~35% β-strand and ~60% unstructured coils. Two conformational states were identified in both alloforms: a collapsed state (CS) that resembles the structural motif of face-to-face hydrophobic clustering in amyloid fibrils, and an extended state (ES) that features the structural characteristics of anti-parallel β-sheets in amyloid oligomers. In Aβ40, the C-terminus remains unstructured and rarely interacts with other parts, thereof the hydrophobic clustering is in loose contact and the peptide assumes ES with high probability. In contrast, the C-terminus of Aβ42 adopts a β-strand structure that strongly interacts with segments E3-R5 and V18-A21. The active association leads to a more compact hydrophobic collapse and refrain the alloform from ES. Based on the structural characterization, we propose that the fibril and oligomer assembly pathways could respectively take off from CS and ES, and their aggregation propensity may be governed by the probability of visiting the corresponding conformational states at the equilibrium.
authors.affiliation: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China.
authors.forename: Wanling
authors.initials: W
authors.lastname: Song
authors.affiliation: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 1] Univ. Grenoble Alpes, IBS, F-38044 Grenoble, France [2] CNRS, IBS, F-38044 Grenoble, France [3] CEA, IBS, F-38044 Grenoble, France.
authors.forename: Jacques-Philippe
authors.initials: JP
authors.lastname: Colletier
authors.affiliation: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China.
authors.forename: Huaiyu
authors.initials: H
authors.lastname: Yang
authors.affiliation: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China.
authors.forename: Yechun
authors.initials: Y
authors.lastname: Xu
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D016000:Cluster Analysis; D057927:Hydrophobic and Hydrophilic Interactions; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)