NMR solution structure of rat aβ(1-16): toward understanding the mechanism of rats' resistance to Alzheimer's disease

Abstract

In an attempt to reveal the mechanism of rats' resistance to Alzheimer's disease, we determined the structure of the metal-binding domain 1-16 of rat β-amyloid (rat Aβ(1-16)) in solution in the absence and presence of zinc ions. A zinc-induced dimerization of the domain was detected. The zinc coordination site was found to involve residues His-6 and His-14 of both peptide chains. We used experimental restraints obtained from analyses of NMR and isothermal titration calorimetry data to perform structure calculations. The calculations employed an explicit water environment and a simulated annealing molecular-dynamics protocol followed by quantum-mechanical/molecular-mechanical optimization. We found that the C-tails of the two polypeptide chains of the rat Aβ(1-16) dimer are oriented in opposite directions to each other, which hinders the assembly of rat Aβ dimers into oligomeric aggregates. Thus, the differences in the structure of zinc-binding sites of human and rat Aβ(1-16), their ability to form regular cross-monomer bonds, and the orientation of their hydrophobic C-tails could be responsible for the resistance of rats to Alzheimer's disease.