Publication
Journal of Chemical Physics
Paper

Different protonated states at the C-terminal of the amyloid- β peptide modulate the stability of S-shaped protofibril

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Abstract

Studies have found strong correlations between polymorphism and structural variations in amyloid-β (Aβ) fibrils and the diverse clinical subtypes of Alzheimer's disease (AD). Thus, a detailed understanding of the conformational behavior of Aβ fibrils may be an aid to elucidate the pathological mechanisms involved in AD. However, a key point that has been inadvertently underestimated or dismissed is the role of the protonated state at the C-terminal residue of amyloid-β peptides, which can give rise to intrinsic differences in the morphology and stability of the fibrils. For instance, the effects of the salt bridge formed between the C-terminal residue A42 and the residue K28 on the S-shaped Aβ protofibril structure remain unknown and may be different from those in the U-shaped Aβ protofibril structures. To address this effect, we explore the stability of the S-shaped protofibrils capped with different C-terminal modifications, including carboxyl group in its deprotonated (COO-) and protonated (COOH) states, by using molecular dynamics simulations. Our findings indicated that the C-terminal deprotonated protofibril is significantly more stable than its C-terminal protonated counterpart due to a well-defined and highly stable zipper-like salt-bridge-chain formed by the ϵ-NH3+ groups on the sidechain of residue K28 and the C-terminal COO- group at the A42 residue. The revealed underlying molecular mechanism for the different stability of the protofibrils provides insights into the diversity of polymorphism in Aβ fibrils.

Date

14 May 2019

Publication

Journal of Chemical Physics

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