Molecular modeling on Zn(II) binding modes of Alzheimer's amyloid β-peptide in insoluble aggregates and soluble complexes

Aggregation of the amyloid beta-peptide (Abeta) into insoluble fibrils is a key pathological event in Alzheimer's disease. Zn(II) ion induces significant Abeta aggregation at nearly physiological concentrations in vitro. In order to explore the induce mechanism, the possible binding modes of Zn(II) in Abeta peptide are studied by molecular modeling method. First, the Abeta species containing 1,2,4 and 12 peptides are established respectively. And next a Zn(II) ion is manually hold the different sits of the Abeta species based on the experimental data and subsequently the coordinate atom and number are assigned. Finally, the optimum binding site is found by the system energy minimization. Modeling results show that in soluble Zn(II) complex, NC of imidazole ring of His14, O of carbonyl of main-chain, and two O of water occupy the four ligand positions of the tetrahedral complex; in the aggregation of Abeta, the His13(Ntau)-Zn(II)-His14(Ntau) bridges are formed by Zn(II) cross-linking action. Therefore, the possible Zn(II) binding mode obtained by the studies will be helpful to reveal the form mechanism of pathogenic aggregates in brain.