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Microsecond molecular dynamics simulation of A?42 and identification of a novel dual inhibitor of A?42 aggregation and BACE1 activity.

ABSTRACT: AIM: To study the conformational changes of A?42 and discover novel inhibitors of both A?42 aggregation and ?-secretase (BACE1). METHODS: A molecular dynamics (MD) simulation at a microsecond level was performed to explore stable conformations of A?42 monomer in aqueous solution. Subsequently, structure-based virtual screening was used to search for inhibitors of both A?42 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 ?-helical conformation of A?42, which was unstable in aqueous solution, turned into a ?-sheet mixed with a coil structure through a transient and fully random coil. The conformation of A?42 mainly comprising ?-sheets and coils structure was used for further virtual screening. Five compounds were identified as inhibitors for A?42 aggregation, and one of them, AE-848, was discovered to be a dual inhibitor of both A?42 aggregation and BACE1, with IC50 values of 36.95 ?mol/L and 22.70 ?mol/L, respectively. CONCLUSION: A helical to ?-sheet conformational change in A?42 occurred in a 1.8 microsecond MD simulation. The resulting ?-sheet structure of the peptide is an appropriate conformation for the virtual screening of inhibitors against A?42 aggregation. Five compounds were identified as inhibitors of A?42 aggregation by in vitro activity assays. It was particularly interesting to discover a dual inhibitor that targets both A?42 aggregation and BACE1, the two crucial players in the pathogenesis of Alzheimer's disease.

SUBMITTER: Wang YY

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

REPOSITORIES: biostudies-literature

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

Wang Yuan-yuan YY Li Li L Chen Tian-tian TT Chen Wu-yan WY Xu Ye-chun YC

Acta pharmacologica Sinica 20130617 9

<h4>Aim</h4>To study the conformational changes of Aβ42 and discover novel inhibitors of both Aβ42 aggregation and β-secretase (BACE1).<h4>Methods</h4>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 inhibit ...[more]

PMID: 23770985

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Project description:Structure and dynamics of voltage-gated ion channels, in particular the motion of the S4 helix, is a highly interesting and hotly debated topic in current membrane protein research. It has critical implications for insertion and stabilization of membrane proteins as well as for finding how transitions occur in membrane proteins-not to mention numerous applications in drug design. Here, we present a full 1 micros atomic-detail molecular dynamics simulation of an integral Kv1.2 ion channel, comprising 120,000 atoms. By applying 0.052 V/nm of hyperpolarization, we observe structural rearrangements, including up to 120 degrees rotation of the S4 segment, changes in hydrogen-bonding patterns, but only low amounts of translation. A smaller rotation ( approximately 35 degrees ) of the extracellular end of all S4 segments is present also in a reference 0.5 micros simulation without applied field, which indicates that the crystal structure might be slightly different from the natural state of the voltage sensor. The conformation change upon hyperpolarization is closely coupled to an increase in 3(10) helix contents in S4, starting from the intracellular side. This could support a model for transition from the crystal structure where the hyperpolarization destabilizes S4-lipid hydrogen bonds, which leads to the helix rotating to keep the arginine side chains away from the hydrophobic phase, and the driving force for final relaxation by downward translation is partly entropic, which would explain the slow process. The coordinates of the transmembrane part of the simulated channel actually stay closer to the recently determined higher-resolution Kv1.2 chimera channel than the starting structure for the entire second half of the simulation (0.5-1 micros). Together with lipids binding in matching positions and significant thinning of the membrane also observed in experiments, this provides additional support for the predictive power of microsecond-scale membrane protein simulations.

Dataset Information

Microsecond molecular dynamics simulation of A?42 and identification of a novel dual inhibitor of A?42 aggregation and BACE1 activity.

Publications

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

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