A micro-environmental study of the Zn(+2)-Aβ1-16 structural properties

Relying on a combination of classical molecular dynamics and hybrid QM/MM computational methods, we study the influence of the nature of the local physico-chemical environment on the structural features of β-amyloid peptides complexed with Zn(+2) ions. The analysis is carried out by comparing among themselves different Zn(+2)-ligand force fields and studying their influence on metal coordination and long-range peptide folding. The system in the non-physiological so-called "gas phase" (no solvent) was also simulated with the purpose of identifying to what extent, if at all, the solvent can affect the Zn coordination mode, besides its long-range structural properties. There are two main results of this investigation. The first is that the Zn(+2) coordination mode in classical molecular dynamics simulations markedly depends on the partial charge attributed to the ion and the atoms surrounding it. Comparing with experiments, it is possible to identify the most appropriate Zn(+2) force field for the Zn(+2)-Aβ1-16 complex in study. Secondly, although the presence of water naturally influences the peptide folding propensity, it does not affect the structure of the Zn(+2) inner coordination shell. A useful way to validate classical results and in particular those referring to the structural differences visible when different force fields are employed, was to use a hybrid QM/MM optimization step. When the classical system configurations are submitted to such a quantum minimization step, the geometries of the resulting Zn(+2) site turn out to be all very similar and structurally in good agreement with what is experimentally known.