Molecular Mechanisms of Alzheimer鈥檚 Biomarker FDDNP Binding to A尾 Amyloid Fibril
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- 作者：Niyati D. Parikh ; Dmitri K. Klimov
- 刊名：Journal of Physical Chemistry B
- 出版年：2015
- 出版时间：September 3, 2015
- 年：2015
- 卷：119
- 期：35
- 页码：11568-11580
- 全文大小：613K
- ISSN：1520-5207
文摘
Using isobaric鈥搃sothermal replica exchange molecular dynamics and the all-atom explicit water model, we examined the binding of FDDNP biomarkers to the A尾 amyloid fibril fragment. Our results can be summarized as follows. First, FDDNP ligands bind with high affinity to the A尾 fibril, and the hydrophobic effect together with 蟺-stacking interactions are the dominant factors governing FDDNP binding. In comparison, electrostatic interactions and hydrogen bonding play a minor role. Second, our simulations reveal a strong tendency of bound FDDNP molecules for self-aggregation. Accordingly, about two-thirds of all bound ligands form aggregated clusters of various sizes, and ligand鈥搇igand interactions make considerable contribution to FDDNP binding. Third, FDDNP ligands bind to two distinct sites on the A尾 fibril. Primary binding sites (NT) are located at the N-terminals of A尾10鈥?0 peptides, whereas secondary ones (CE) occur on the concave fibril edge near fibril channels. The NT sites are characterized by strong hydrophobic and 蟺-stacking interactions, favorable binding entropy resulting from multiple FDDNP binding orientations and propensity for self-aggregation but relatively weak van der Waals interactions. In contrast, the CE sites offer stronger van der Waals binding interactions but weaker hydrophobic and aromatic interactions and less favorable binding entropy. By comparing our data with previous studies, we suggest that the primary binding locations identified by us are likely to occur in other A尾 fibril polymorphic structures. We also show that FDDNP binds via distinct mechanisms to A尾 fibrils and monomers. We argue that FDDNP binds with stronger affinity to benign A尾 monomers than to the fibrils, raising questions about the ability of FDDNP to selectively label amyloid deposits.