Effect of mutation on Aβ1-42-Heme complex in aggregation mechanism: Alzheimer's disease

Abstract

Amyloid β (Aβ) peptide aggregation is one of the root causes for Alzheimer's disease. Recently, experimental studies show that three active binding sites (His6, His13 and His14) of Aβ peptides were bound with heme to form Aβ-Heme complex, which leads to inhibit the aggregation process. We apply molecular dynamic simulation to investigate the aggregation pathways of Aβ-Heme peptides. The above three binding sites were mutated by Glycine residue individually and generate three complex systems such as Aβ(His6Gly)-Heme, Aβ(His13Gly)-Heme and Aβ(His14Gly)-Heme. These complexes were simulated in explicit water using gromos53a6 force field for 200ns. We found that the His13Gly mutation increase the β-sheet contents (75%) in Aβ peptide. On the other hand, heme binds with His13 residue of native peptide plays an important role to reduce the formation β-sheet content (50%) in Aβ peptide. This finding is in agreement with experimental study, which showed that the effect of mutation on His6 is not directly involved in β-sheet formation, but the effect of mutation in His13 and His14 has involved in β-sheet formation [J. Neurochem. (2009), 110, 1784-1795]. So, our results may be useful to understand the pathway mechanism of aggregation of Aβ peptides.

Keywords: Alzheimer’s disease; Aβpeptides; Heme; His13Gly mutation; Molecular dynamic simulation.