科研之友
微信
新浪微博
Facebook
分享链接
摘要
Alzheimer's disease (AD) is mainly caused by the aggregation of amyloid-beta (A beta) protein. Development of inhibitors to prevent A beta aggregation is the most efficient method to devise a cure for AD. A beta aggregation has been found to be inhibited by the affibody protein Z(A beta 3), selected via phage display. However, the molecular basis of affinity interactions between A beta and Z(A beta 3), the interaction region, and important residues of A beta and Z(A beta 3) 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 A beta and Z(A beta 3). Interactions between the beta-strand of Z(A beta 3) and A beta(16-40) were found to contribute greatly to their binding free energy, while that between the alpha-helix of Z(A beta 3) and Z(A beta 3) has a smaller contribution. Based on the free energy decomposition, hotspot residues of Z(A beta 3) are E15, 116, V17, Y18, L19, P20, N21, and L22 and those of A beta(16-40) include F19, F20, A21, E22, D23, K28, 131, 132, G33, L34, M35, V36, G38, and V40. Z(A beta 3) stabilizes the beta-sheet by burying the two mostly nonpolar faces of the A beta hairpin within a large hydrophobic tunnel-like cavity formed by the alpha-helix. The identified binding motif can be used as a starting point for rational design of protein inhibitors with high affinity for A beta to prevent A beta aggregation. The three key characteristics of efficient protein inhibitors are the presence of a high-affinity site (beta-strand), a large accessory structure (alpha-helix), and a stable conformation owing to disulfide bonds. The high-affinity site can competitively bind to the A beta monomer, and the large accessory structure can block other A beta monomers; both these elements require a stable conformation via disulfide bonds. These three characteristics of a protein inhibitor can be employed together to suppress A beta aggregation.
