期刊
JOURNAL OF PHYSICAL CHEMISTRY B
卷 120, 期 47, 页码 12088-12097出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jpcb.6b09655
关键词
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资金
- National Science Foundation [CHE-1363320]
- Alexander von Humboldt Foundation
- Office of Science of the U.S. Department of Energy [DE-AC02-05CH11231]
In this work, we characterize the nucleation and elongation mechanisms of the diseased polymorph of the amyloid-beta 40 (A beta 40) fibril using an off-lattice coarse-grained (CG) protein model. After determining the nucleation size and subsequent stable protofibrillar structure from the CG model, validated with all-atom simulations, we consider the lock and dock and activated monomer fibril elongation mechanisms for the protofibril by statistical additions of a monomer drawn from four different ensembles of the free A beta 40 peptide to grow the fibril. Our CG model shows that the dominant mechanism for fibril elongation is the lock and dock mechanism across all monomer ensembles, even when the monomer is in the activated form. Although our CG model finds no thermodynamic difference between the two fibril elongation mechanisms, the activated monomer is found to be kinetically faster by a factor of 2 for the locking step compared with all other structured or unstructured monomer ensembles.
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