Structures and free energy landscapes of aqueous zinc(II)-bound amyloid-?(1-40) and zinc(II)-bound amyloid-?(1-42) with dynamics.

ABSTRACT: Binding of divalent metal ions with intrinsically disordered fibrillogenic proteins, such as amyloid-? (A?), influences the aggregation process and the severity of neurodegenerative diseases. The A? monomers and oligomers are the building blocks of the aggregates. In this work, we report the structures and free energy landscapes of the monomeric zinc(II)-bound A?40 (Zn:A?40) and zinc(II)-bound A?42 (Zn:A?42) intrinsically disordered fibrillogenic metallopeptides in an aqueous solution by utilizing an approach that employs first principles calculations and parallel tempering molecular dynamics simulations. The structural and thermodynamic properties, including the secondary and tertiary structures and conformational Gibbs free energies of these intrinsically disordered metallopeptide alloforms, are presented. The results show distinct differing characteristics for these metallopeptides. For example, prominent ?-sheet formation in the N-terminal region (Asp1, Arg5, and Tyr10) of Zn:A?40 is significantly decreased or lacking in Zn:A?42. Our findings indicate that blocking multiple reactive residues forming abundant ?-sheet structure located in the central hydrophobic core and C-terminal regions of Zn:A?42 via antibodies or small organic molecules might help to reduce the aggregation of Zn(II)-bound A?42. Furthermore, we find that helix formation increases but ?-sheet formation decreases in the C-terminal region upon Zn(II) binding to A?. This depressed ?-sheet formation in the C-terminal region (Gly33-Gly38) in monomeric Zn:A?42 might be linked to the formation of amorphous instead of fibrillar aggregates of Zn:A?42.

SUBMITTER: Wise-Scira O 

PROVIDER: S-EPMC4886726 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature