期刊
ACS CHEMICAL NEUROSCIENCE
卷 10, 期 3, 页码 1347-1354出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.8b00425
关键词
Amyloid forming peptide; mutation effect on rate of aggregation; Alzheimer's disease; free energy for alpha-helix to beta-sheet interconversion; umbrella sampling simulations; familial mutations
资金
- Swedish Foundation for Strategic Research (SSF) through the project New imaging biomarkers in early diagnosis and treatment of Alzheimer's disease
- SLL through the project Biomolecular pro-filing for early diagnosis of Alzheimer's disease
- Swedish Infrastructure Committee (SNIC) [SNIC2017-12-49, SNIC2018-3-3]
- VR-DST [2015-06726]
- DST-VR [DST/NTSWD/VR/P-03/2016]
Understanding the initial events of aggregation of amyloid beta monomers to form beta-sheet rich fibrils is useful for the development of therapeutics for Alzheimer's disease. In this context, the changes in energetics involved in the aggregation of helical amyloid beta monomers into beta-sheet rich dimers have been investigated using umbrella sampling simulations and density functional theory calculations. The results from umbrella sampling simulations for the free energy profile for the interconversion closely agree with the results of density functional theory calculations. The results reveal that helical peptides converted to beta-sheet structures through coil-like conformations as intermediates that are mostly stabilized by intramolecular hydrogen bonds. The stabilization of intermediate structures could be a possible way to inhibit fibril formation. Mutations substantially decrease the height of the energy barrier for interconversion from alpha-helix to beta-sheet structure when compared to that of the wild type, something that is attributed to an increase in the number of intramolecular hydrogen bonds between backbone atoms in the coil structures that correspond to a maximum value on the free energy surface. The reduction of the energy barrier leads to an enhancement of the rate of aggregation of amyloid beta monomers upon introduction of various familial mutations, which is consistent with previous experimental reports.
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