9,10-Anthraquinone hinders -aggregation: How does a small molecule interfere with A-peptide amyloid fibrillation?

Marino Convertino 1 2, Riccardo Pellarin 1 *, Marco Catto 2, Angelo Carotti 2, Amedeo Caflisch 1 *

1Department of Biochemistry, University of Zurich, CH-8057 Zurich, Switzerland 2Dipartimento Farmaco-Chimico, Università degli Studi di Bari, I-70125 Bari, Italy

email: Riccardo Pellarin (pellarin@bioc.uzh.ch) Amedeo Caflisch (caflisch@bioc.uzh.ch)

^*Correspondence to Riccardo Pellarin, Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland

^*Correspondence to Amedeo Caflisch, Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland

Funded by:
 Ministry of University and Scientific Research, Rome, Italy (FIRB project); Grant Number: RBAU01LSCE
 Swiss National Competence Center in Neural Plasticity and Repair

Amyloid aggregation is linked to a number of neurodegenerative syndromes, the most prevalent one being Alzheimer's disease. In this pathology, the -amyloid peptides (A) aggregate into oligomers, protofibrils, and fibrils and eventually into plaques, which constitute the characteristic hallmark of Alzheimer's disease. Several low-molecular-weight compounds able to impair the A aggregation process have been recently discovered; yet, a detailed description of their interactions with oligomers and fibrils is hitherto missing. Here, molecular dynamics simulations are used to investigate the influence of two relatively similar tricyclic, planar compounds, that is, 9, 10-anthraquinone (AQ) and anthracene (AC), on the early phase of the aggregation of the A heptapeptide segment H14QKLVFF20, the hydrophobic stretch that promotes the A self-assembly. The simulations show that AQ interferes with -sheet formation more than AC. In particular, AQ intercalates into the -sheet because polar interactions between the compound and the peptide backbone destabilize the interstrand hydrogen bonds, thereby favoring disorder. The thioflavin T-binding assay indicates that AQ, but not AC, sensibly reduces the amount of aggregated A1-40 peptide. Taken together, the in silico and in vitro results provide evidence that structural perturbations by AQ can remarkably affect ordered oligomerization. Moreover, the simulations shed light at the atomic level on the interactions between AQ and A oligomers, providing useful insights for the design of small-molecule inhibitors of aggregation with therapeutic potential in Alzheimer's disease.