Characterization of the polymorphic states of copper(II)-bound Aβ(1-16) peptides by computational simulations

Understanding the polymorphic states of metal amyloid β (Aβ) interactions helps to elucidate metal-mediated events in the pathogenesis of Alzheimer's disease. Systematic investigations on the effects of metal ions such as Cu(2+) and Zn(2+) on the structural and thermodynamic properties of Aβ at the molecular lever seem desirable. In this study, a set of new AMBER force field parameters was developed to model various Cu(2+) coordination spheres of Aβ. These parameters including force constants and partial charges obtained using restrained electrostatic potential method were then validated in replica-exchange molecular dynamics simulations on six Cu(2+)-Aβ(1-16) systems. The Cu(2+) coordination geometry differs depending on the Cu(2+) binding fashions. The structural analyses reveal that Aβ(1-16) prefers turn conformations, which provides a geometrical favor to establish multiple Cu(2+) coordination modes in solution at physiological pH. The relative stability of different Cu(2+)-Aβ(1-16) complexes was estimated by free energy calculations. The Cu(2+) ligands in the most stable Cu(2+)-Aβ(1-16) structure involve Glu(3) , His(6) , His(13) and His(14) in terms of MM/3D-RISM (molecular mechanics/three-dimensional reference interaction site model). The solvation free energy and conformational entropy calculated by 3D-RISM method suggest that the binding of Cu(2+) within Aβ(1-16) is a spontaneous process. The overlap of the preparation free energy distributions demonstrates the heterogeneous states of Aβ(1-16) conformations that are ready for Cu(2+) binding whereas the populations of such polymorphic states may shift at differing pH.