期刊
ACS OMEGA
卷 4, 期 1, 页码 892-903出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsomega.8b02672
关键词
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资金
- University Grants Commission, New Delhi under the UGC-SAP-DRS Phase-II scheme
- DST SERB
- UGC under UGC-BSR scheme
- DST PURSE-II scheme
Aggregation of amyloid beta (A beta) peptides leads to formation of fibrilar, soluble oligomers, and their deposition is a key event in progression of Alzheimer's disease (AD). Recent experimental studies of Arg-Arg-7-amino-4-trifluoromethylcoumarin (RR-AFC) showed significant A beta aggregation inhibition, but its molecular mechanism is not yet clear. Hence, the present study aims at exploring the underlying mechanism of destabilization and inhibition of aggregation of the A beta protofibril by RR-AFC at the molecular level. Molecular docking analysis shows that RR-AFC binds to chain A of the A beta protofibril through hydrogen bonding interactions. Comparative molecular dynamics simulations depict the binding of RR-AFC at the edge of chain A, and its partially inserted conformation at the hydrophobic core destabilizes the A beta protofibril. Its binding causes loss of hydrophobic contacts, leading to a partial opening of tightly packed beta-sheet protofibrils. The hydration effect of salt bridge between the amino group of Lys28 and the oxygen atom of RR-AFC contributes in destabilization of A beta protofibrils. Binding free energy calculations of RR-AFC and the A beta protofibril showed that van der Waals interactions are dominant over the others. Thus, our results revealed that RR-AFC interacts mainly with the hydrophobic core along with positively charged residues of the A beta protofibril for effective destabilization. Thus, this structural information could be useful to design new inhibitors to control the aggregation of A beta protofibrils in AD patients.
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