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 Cu2+ and Zn2+ 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 Cu2+ 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 Cu2+-Aβ(1–16) systems. The Cu2+ coordination geometry differs depending on the Cu2+ binding fashions. The structural analyses reveal that Aβ(1–16) prefers turn conformations, which provides a geometrical favor to establish multiple Cu2+ coordination modes in solution at physiological pH. The relative stability of different Cu2+-Aβ(1–16) complexes was estimated by free energy calculations. The Cu2+ ligands in the most stable Cu2+-Aβ(1–16) structure involve Glu3, His6, His13 and His14 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 Cu2+ 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 Cu2+ binding whereas the populations of such polymorphic states may shift at differing pH. © 2013 Wiley Periodicals, Inc.