Structural and Electronic Analysis of the Octarepeat Region of Prion Protein with Four Cu(II) by Polarizable MD and QM/MM Simulations

The prion protein, located mainly in neurons, is believed to play the role of metal ion transporter. A 32-residue region of the N-terminal domain, known as octarepeat, can bind up to four Cu ions. Different coordination modes have been observed and are strongly dependent on Cu concentration. Many theoretical studies carried out so far have focused on studying the coordination modes of a single copper ion. In this work we investigate the octarepeat region coordinated with four copper ions. Molecular dynamics (MD) and hybrid quantum mechanics/molecular mechanics (QM/MM) simulations using the polarizable AMOEBA force field have been carried out. Results indicate that the 4Cu-octarepeat complex forms a globular structure, in agreement with experimental results. Subsequent QM/MM simulations on several snapshots suggests the system is in a high-spin quintet state, with all Cu ions bearing one single electron, and all unpaired electrons are ferromagnetically coupled.