Citation: LIU Fu-Feng, FAN Yu-Bo, LIU Zhen, BAI Shu. Molecular Mechanism Underlying Affinity Interactions between Z_Aβ3 and the A_β16-40 Monomer[J]. Acta Physico-Chimica Sinica, ;2017, 33(9): 1905-1914. doi: 10.3866/PKU.WHXB201704274 shu

Molecular Mechanism Underlying Affinity Interactions between Z_Aβ3 and the A_β16-40 Monomer

LIU Fu-Feng ^1,2,3,4, ,
FAN Yu-Bo ¹ ,
LIU Zhen ¹ ,
BAI Shu ¹

1.
Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P. R. China;
2.
Key Laboratory of Industrial Fermentation Microbiology Ministry of Education, Tianjin 300457, P. R. China;
3.
National and Local United Engineering Lab of Metabolic Control Fermentation Technology, Tianjin 300457, P. R. China;
4.
College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, P. R. China

Received Date: 26 January 2017
Revised Date: 19 April 2017

Fund Project: The project was supported by the National Natural Science Foundation of China (21576199).

Alzheimer's disease (AD) is mainly caused by the aggregation of amyloid-β (Aβ) protein. Development of inhibitors to prevent Aβ aggregation is the most efficient method to devise a cure for AD. Aβ aggregation has been found to be inhibited by the affibody protein Z_Aβ3, selected via phage display. However, the molecular basis of affinity interactions between Aβ and Z_Aβ3, the interaction region, and important residues of Aβ and Z_Aβ3 remain unclear. Herein, molecular dynamics simulations and free energy calculation and decomposition using the molecular mechanics-Poisson-Boltzmann surface area method (MM-PBSA) were coupled to investigate the molecular mechanism underlying interactions between Aβ and Z_Aβ3. Interactions between the β-strand of Z_Aβ3 and A_β16-40 were found to contribute greatly to their binding free energy, while that between the α-helix of Z_Aβ3 and Z_Aβ3 has a smaller contribution. Based on the free energy decomposition, hotspot residues of Z_Aβ3 are E15, I16, V17, Y18, L19, P20, N21, and L22 and those of A_β16-40 include F19, F20, A21, E22, D23, K28, I31, I32, G33, L34, M35, V36, G38, and V40. Z_Aβ3 stabilizes the β-sheet by burying the two mostly nonpolar faces of the Aβ hairpin within a large hydrophobic tunnel-like cavity formed by the α-helix. The identified binding motif can be used as a starting point for rational design of protein inhibitors with high affinity for Aβ to prevent Aβ aggregation. The three key characteristics of efficient protein inhibitors are the presence of a high-affinity site (β-strand), a large accessory structure (α-helix), and a stable conformation owing to disulfide bonds. The high-affinity site can competitively bind to the Aβ monomer, and the large accessory structure can block other Aβ monomers; both these elements require a stable conformation via disulfide bonds. These three characteristics of a protein inhibitor can be employed together to suppress Aβ aggregation.
- Protein inhibitor,
- Amyloid-β protein,
- Molecular dynamics simulation,
- Free energy decomposition,
- Molecular mechanism
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Molecular Mechanism Underlying Affinity Interactions between ZAβ3 and the Aβ16-40 Monomer

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通讯作者: 陈斌, bchen63@163.com

Molecular Mechanism Underlying Affinity Interactions between Z_Aβ3 and the A_β16-40 Monomer