Revisiting Cu(II) Bound Amyloid-β40 and Amyloid-β42 Peptides: Varying Coordination Chemistries

Abstract

Metal ions and intrinsically disordered peptides amyloid-β40 and amyloid-β42 are at thecenter of Alzheimer´s disease pathology. Divalent copper ion binds to amyloid-β40 and amyloid-β42peptides with varying coordination chemistries. Experiments face challenges in the measurements ofdivalent copper ion bound monomeric amyloid-β40 and amyloid-β42 in an aqueous solution mediumbecause of fast conformational changes, rapid aggregation processes and solvent effects. Theoreticalstudies complement experiments and provide insights at the atomic and molecular levels withdynamics. However, until recently, potential functions for simulating divalent copper ion boundamyloid-β40 and amyloid-β42 peptides with varying coordination chemistries were lacking. Usingnew potential functions that were developed for divalent copper centers, Cu(II), including threehistidine residues and an oxygen-ligated amino acid residue, the structures and thermodynamicproperties of Cu(II)-bound amyloid-β40 and amyloid-β42 peptides in an aqueous solution mediumwere studied. For these purposes, extensive first principles calculations and replica exchangemolecular dynamics simulations were conducted. In this study, the secondary and tertiary structuralproperties, conformational Gibbs free energy values, potential of mean force surfaces, salt bridgesand aggregation propensities of aqueous Cu(II)-bound amyloid-β40 and amyloid-β42 peptides arepresented. Different than previous findings in the literature, results clearly show that the coordinationchemistry variations impact the structural and thermodynamic properties of divalent Cu(II) boundamyloid-β alloforms in water. Specificities about these differences are revealed in this study at theatomic level with dynamics. Results presented herein are the first to offer a comparison of themonomeric Cu(II)-bound amyloid-β40 and amyloid-β42 peptides with varying coordinationchemistries using bonded model potential functions.