Structure and Dynamics of Amyloid-β Segmental Polymorphisms

Abstract

It is believed that amyloid-beta (Aβ) aggregates play a role in the pathogenesis of Alzheimer’s disease. Aβ molecules form β-sheet structures with multiple interaction sites. This polymorphism gives rise to differences in morphology, physico-chemical property and level of cellular toxicity. We have investigated the conformational stability of various segmental polymorphisms using molecular dynamics simulations and find that the segmental polymorphic models of Aβ retain a U-shaped architecture. Our results demonstrate the importance of inter-sheet side chain-side chain contacts, hydrophobic contacts among the strands (β1 and β2) and of salt bridges in stabilizing the aggregates. Residues in β-sheet regions have smaller fluctuation while those at the edge and loop region are more mobile. The inter-peptide salt bridges between Asp23 and Lys28 are strong compared to intra-chain salt bridge and there is an exchange of the inter-chain salt-bridge with intra-chain salt bridge. As our results suggest that Aβ exists under physiological conditions as an ensemble of distinct segmental polymorphs, it may be necessary to account in the development of therapeutics for Alzheimer’s disease the differences in structural stability and aggregation behavior of the various Aβ polymorphic forms.

On the lack of polymorphism in Aβ‐peptide aggregates derived from patient brains

“…The difference between the in vivo and in vitro fibril models also questions the relevance of previous computational studies that were based on the in vitro models and explored the effect of mutations, alternate fibril morphologies, or nucleation, in cross-seeding or for in silico structure-based search of inhibitors or imaging agents. [8][9][10][11][12] Our simulations indicate that the brain-derived model is less stable than the two in vitro models. The three-fold in vivo and in vitro fibril models are characterized by a central hydrated channel that may explain the toxicity of the amyloids as such channels interfere with nerve cells communication by changing membrane potential, and also may cause cell death because of loss of solutes.…”

Side‐chain hydrophobicity and the stability of Aβ16–22 aggregates

“…We use fully atomic molecular dynamics simulations to investigate the effect of widely used force fields (AMBER 03, AMBER99SB, AMBER99SB-ILDN, CHARMM27, GROMOS96-53a6, and OPLS-AA/L) on structural properties of the Ab [16][17][18][19][20][21][22] aggregates from fibril model. The distribution of Ab monomers, the early stages of oligomerization, and their dependence on sequence (i.e., mutations) and environment, [30][31][32][33][34] the mechanism of Ab fibril disassembly, [35][36][37][38] and the early steps of Ab monomer deposition on fibril fragments [39][40][41][42] have been studied extensively in silico. A wide range of models including protein coarsegrained lattice, 43 off-lattice models, 44 and all-atom force fields 45 have been used to explore the different stages of oligomerization.…”

Stability of Amyloid Oligomers

“…3). We have investigated the packing and stability of the different models in a series of molecular dynamics simulations (Berhanu & Hansmann, 2012b) and have shown that the stability of these amyloid aggregates depends strongly on the length of the steric zipper, hydrophobicity, and the number of side chains involved at a β-sheet-β-sheet interface. However, all our models retain their original U shape which is consistence with experimental observation of various polymorphic forms in vitro (Meinhardt et al, 2009).…”

“…Even though such studies do not involve amyloid assembly, they provide indirect input into the various factors that contribute to or modulate fibril formation. Examples are the nucleation and growth mechanisms of fibril-like oligomers Kahler, Sticht, & Horn, 2013), polymorphism (alternative interfaces) (Berhanu & Hansmann, 2012b;Miller, Ma, & Nussinov, 2011aWu, Bowers, & Shea, 2010), the effects of mutations (Blinov, Dorosh, Wishart, & Kovalenko, 2010;Kassler, Horn, & Sticht, 2010), thermodynamic stability (Blinov et al, 2010), and interactions with membranes ( Jang et al, 2013). We will therefore focus in this review on stability studies of preformed amyloid aggregates in explicit water and show that such simulations can not only explain experimental observations but also guide future experiments Mousseau & Derreumaux, 2005).…”