A theoretical study on the molecular determinants of the affibody protein Z(A beta 3) bound to an amyloid beta peptide

作者：Wang Xu; Sun Xianqiang; Kuang Guanglin; Agren Hans; Tu Yaoquan^*

来源：Physical Chemistry Chemical Physics, 2015, 17(26): 16886-16893.

DOI：10.1039/c5cp00615e

Amyloid beta (A beta) peptides are small cleavage products of the amyloid precursor protein. Aggregates of A beta peptides are thought to be linked with Alzheimer's and other neurodegenerative diseases. Strategies aimed at inhibiting amyloid formation and promoting A beta clearance have been proposed and investigated in in vitro experiments and in vivo therapies. A recent study indicated that a novel affibody protein Z(A beta 3), which binds to an A beta 40 monomer with a binding affinity of 17 nM, is able to prevent the aggregation of A beta 40. However, little is known about the energetic contribution of each residue in Z(A beta 3) to the formation of the (Z(A beta 3))(2):A beta complex. To address this issue, we carried out unbiased molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area calculations. Through the per-residue decomposition scheme, we identified that the van der Waals interactions between the hydrophobic residues of (Z(A beta 3))(2) and those at the exterior and interior faces of A beta are the main contributors to the binding of (Z(A beta 3))(2) to A beta. Computational alanine scanning identified 5 hot spots, all residing in the binding interface and contributing to the binding of (Z(A beta 3))(2) to A beta through the hydrophobic effect. In addition, the amide hydrogen bonds in the 4-strand beta-sheet and the pi-pi stacking were also analyzed. Overall, our study provides a theoretical basis for future experimental improvement of the Z(A beta 3) peptide binding to A beta.

• 出版日期2015