ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Molecular dynamic studies of amyloid-beta interactions with curcumin and Cu2+ ions

Stanislav Kozmon and Igor Tvaroška

Institute of Chemistry, Slovak Academy of Sciences, Dúbravská cesta 9, Bratislava 845 38, Slovakia

E-mail: chemitsa@savba.sk

Abstract: Amyloid-beta (Aβ) peptide readily forms aggregates that are associated with Alzheimer’s disease. Transition metals play a key role in this process. Recently, it has been shown that curcumin (CUA), a polyphenolic phytochemical, inhibits the aggregation of Aβ peptide. However, interactions of Aβ peptide with metal ions or CUA are not entirely clear. In this work, molecular dynamics (MD) simulations were carried out to clear the nature of interactions between the 42-residue Aβ peptide (Aβ-42) and Cu²⁺ ions and CUA. Altogether nine different models were investigated, and more than 2 μs of the simulation data were analyzed. The models represent the possible modes of arrangement between Aβ-42 and Cu²⁺ ions and CUA, respectively, and were used to shed light on the Aβ-42 conformational behavior in the presence of Cu²⁺ ions and CUA molecules. Obtained data clearly showed that the presence of a CUA molecule or a higher concentration of copper ions significantly affect the conformational behavior of Aβ-42. Calculations showed that the change of the His13 protonation state (Aβ(H13δ)-Cu²⁺, Aβ(H13δ)-Cu²⁺-CUA models) leads to higher occurrence of the Asp23-Lys28 salt bridge. Analyzes of trajectories revealed that C-terminal β-sheet structures occurred significantly less frequently, and CUA promoted the stabilization of the α-helical structure. Further, calculations of the Aβ-42 complex with CUA and Cu²⁺ ions showed that CUA can chelate the Cu²⁺ ion and directly interact with Aβ, which may explain why CUA acts as an inhibitor of Aβ aggregation.

Keywords: Alzheimers’s disease – amyloid beta – molecular dynamics – curcumin

Full paper is available at www.springerlink.com.

DOI: 10.1515/chempap-2015-0134

Chemical Papers 69 (9) 1262–1276 (2015)