Acta Phys. -Chim. Sin. ›› 2017, Vol. 33 ›› Issue (9): 1905-1914.doi: 10.3866/PKU.WHXB201704274

• ARTICLE • Previous Articles     Next Articles

Molecular Mechanism Underlying Affinity Interactions between ZAβ3 and the Aβ16-40 Monomer

Fu-Feng LIU1,2,3,4,Yu-Bo FAN1,Zhen LIU1,Shu BAI1,*()   

  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:2017-01-26 Published:2017-07-05
  • Contact: Shu BAI
  • 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 ZAβ3, selected via phage display. However, the molecular basis of affinity interactions between Aβ and ZAβ3, the interaction region, and important residues of Aβ and ZAβ3 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 ZAβ3. Interactions between the β-strand of ZAβ3 and Aβ16-40 were found to contribute greatly to their binding free energy, while that between the α-helix of ZAβ3 and ZAβ3 has a smaller contribution. Based on the free energy decomposition, hotspot residues of ZAβ3 are E15, I16, V17, Y18, L19, P20, N21, and L22 and those of Aβ16-40 include F19, F20, A21, E22, D23, K28, I31, I32, G33, L34, M35, V36, G38, and V40. ZAβ3 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.

Key words: Protein inhibitor, Amyloid-β protein, Molecular dynamics simulation, Free energy decomposition, Molecular mechanism


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