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

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Abstract

Binding of divalent metal ions with intrinsically disordered fibrillogenic proteins, such as amyloid-β (Aβ), influences the aggregation process and the severity of neurodegenerative diseases. The Aβ 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 Aβ40 (Zn:Aβ40) and zinc(II)-bound Aβ42 (Zn:Aβ42) 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 β-sheet formation in the N-terminal region (Asp1, Arg5, and Tyr10) of Zn:Aβ40 is significantly decreased or lacking in Zn:Aβ42. Our findings indicate that blocking multiple reactive residues forming abundant β-sheet structure located in the central hydrophobic core and C-terminal regions of Zn:Aβ42 via antibodies or small organic molecules might help to reduce the aggregation of Zn(II)-bound Aβ42. Furthermore, we find that helix formation increases but β-sheet formation decreases in the C-terminal region upon Zn(II) binding to Aβ. This depressed β-sheet formation in the C-terminal region (Gly33–Gly38) in monomeric Zn:Aβ42 might be linked to the formation of amorphous instead of fibrillar aggregates of Zn:Aβ42.

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Acknowledgments

This research was supported by an allocation and computing resources provided with the help of the National Institute for Computational Sciences (grant TG-CHE110044). The calculations and simulations were performed on Kraken at the National Institute for Computational Sciences and Ranger at the Texas Advanced Computing Center. G.P. is thankful for the financial support provided by the National Institutes of Health (G12-RR013646), the RCMI Center for Interdisciplinary Health Research, and the Alzheimer’s Association. O.C. is thankful for support from the University of Texas at San Antonio and the Neuroscience Institute of the San Antonio Life Sciences Institute (Charles Wilson) at the University of Texas at San Antonio. We also thank Carlos Gonzalez (NIST) for helpful discussions.

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Authors and Affiliations

  1. Department of Chemistry, The University of Texas at San Antonio, One UTSA Circle, San Antonio, TX, 78249, USA

    Olivia Wise-Scira, Liang Xu & Orkid Coskuner

  2. Neurosciences Institute, The University of Texas at San Antonio, One UTSA Circle, San Antonio, TX, 78249, USA

    George Perry & Orkid Coskuner

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  1. Olivia Wise-Scira
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Correspondence to Orkid Coskuner.

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Wise-Scira, O., Xu, L., Perry, G. et al. Structures and free energy landscapes of aqueous zinc(II)-bound amyloid-β(1–40) and zinc(II)-bound amyloid-β(1–42) with dynamics. J Biol Inorg Chem 17, 927–938 (2012). https://doi.org/10.1007/s00775-012-0909-9

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