Microsecond molecular dynamics simulation of Aβ42 and identification of a novel dual inhibitor of Aβ42 aggregation and BACE1 activity.

ABSTRACT:

Aim

To study the conformational changes of Aβ42 and discover novel inhibitors of both Aβ42 aggregation and β-secretase (BACE1).

Methods

A molecular dynamics (MD) simulation at a microsecond level was performed to explore stable conformations of Aβ42 monomer in aqueous solution. Subsequently, structure-based virtual screening was used to search for inhibitors of both Aβ42 aggregation and BACE1. Protein purification and in vitro activity assays were performed to validate the inhibition of the compounds identified via virtual screening.

Results

The initial α-helical conformation of Aβ42, which was unstable in aqueous solution, turned into a β-sheet mixed with a coil structure through a transient and fully random coil. The conformation of Aβ42 mainly comprising β-sheets a

SUBMITTER: Wang YY 

PROVIDER: S-EPMC4003156 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature