Modeling Copper Binding to the Amyloid‑β Peptide at Different pH: Toward a Molecular Mechanism for Cu Reduction Sara Furlan, † Christelle Hureau, † Peter Faller, † and Giovanni La Penna* ,‡ † LCC - Laboratory of coordination chemistry, CNRS - National Center for Scientific Research, 205 route de Narbonne, F-31077 Toulouse, France ‡ ICCOM - Institute for chemistry of organo-metallic compounds, CNR - National Research Council of Italy, via Madonna del Piano 10, I-50019 Sesto Fiorentino, Firenze, Italy * S Supporting Information ABSTRACT: Oxidative stress, including the production of reactive oxygen species (ROS), has been reported to be a key event in the etiology of Alzheimer’s disease (AD). Cu has been found in high concentrations in amyloid plaques, a hallmark of AD, where it is bound to the main constituent amyloid-β (Aβ) peptide. Whereas it has been proposed that Cu-Aβ complexes catalyze the production of ROS via redox-cycling between the Cu(I) and Cu(II) state, the redox chemistry of Cu-Aβ and the precise mechanism of redox reactions are still unclear. Because experiments indicate different coordination environments for Cu(II) and Cu(I), it is expected that the electron is not transferred between Cu-Aβ and reactants in a straightforward manner but involves structural rearrangement. In this work the structures indicated by experimental data are modeled at the level of modern density- functional theory approximations. Possible pathways for Cu(II) reduction in different coordination sites are investigated by means of first-principles molecular dynamics simulations in the water solvent and at room temperature. The models of the ligand reorganization around Cu allow the proposal of a preferential mechanism for Cu-Aβ complex reduction at physiological pH. Models reveal that for efficient reduction the deprotonated amide N in the Ala 2-Glu 3 peptide bond has to be protonated and that interactions in the second coordination sphere make important contributions to the reductive pathway, in particular the interaction between COO - and NH 2 groups of Asp 1. The proposed mechanism is an important step forward to a clear understanding of the redox chemistry of Cu-Aβ, a difficult task for spectroscopic approaches as the Cu-peptide interactions are weak and dynamical in nature. ■ INTRODUCTION Copper ions play a key role in a multitude of biological processes, mostly in the active center of enzymes where a major function is in electron transfer reactions and/or substrate binding. Most prominent are superoxide dismutase and cytochrome c oxidase. In biology, copper can occur in two stable redox states, Cu(I) and Cu(II). The redox reactions are mostly restricted to these two redox states and hence include a one electron transfer per Cu ion. These ions are classically strongly bound in the enzymes, in both thermodynamic and kinetic sense. Loosely bound or free Cu ions can undergo uncontrolled redox reactions and are able to promote the reduction of dioxygen, and hence the production of reactive oxygen species (ROS), which are potentially harmful to cells due to their reaction with proteins, nucleic acids, and lipids. To avoid these last reactions, the Cu metabolism is tightly controlled with the help of Cu transmembrane transporters and Cu chaperones (intracellular carriers). 1-4 Under stress or disease conditions, Cu homeostasis can be affected, leading to more loosely bound Cu, prone to ROS production. 5 This is thought to be the case in neuro- degenerative disorders, 6 including Alzheimer ’ s disease (AD), 7-9 where a high concentration of Cu is found in amyloid plaques, a hallmark of this disease. Cu is bound to the main constituent, the peptide amyloid-β (Aβ). 10 Thus, it is thought that Cu is bound to Aβ under AD conditions, and it Received: September 10, 2012 Revised: September 13, 2012 Published: September 13, 2012 Article pubs.acs.org/JPCB © 2012 American Chemical Society 11899 dx.doi.org/10.1021/jp308977s | J. Phys. Chem. B 2012, 116, 11899-11910