A theoretical study on the molecular determinants of the affibody protein ZAbeta3 bound to an amyloid beta peptide.
2015 (English)In: Physical chemistry chemical physics : PCCP, Vol. 17, no 26, 16886-16893 p.Article in journal (Refereed) Published
Amyloid beta (Abeta) peptides are small cleavage products of the amyloid precursor protein. Aggregates of Abeta peptides are thought to be linked with Alzheimer's and other neurodegenerative diseases. Strategies aimed at inhibiting amyloid formation and promoting Abeta clearance have been proposed and investigated in in vitro experiments and in vivo therapies. A recent study indicated that a novel affibody protein ZAbeta3, which binds to an Abeta40 monomer with a binding affinity of 17 nM, is able to prevent the aggregation of Abeta40. However, little is known about the energetic contribution of each residue in ZAbeta3 to the formation of the (ZAbeta3)2:Abeta 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 (ZAbeta3)2 and those at the exterior and interior faces of Abeta are the main contributors to the binding of (ZAbeta3)2 to Abeta. Computational alanine scanning identified 5 hot spots, all residing in the binding interface and contributing to the binding of (ZAbeta3)2 to Abeta 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 ZAbeta3 peptide binding to Abeta.
Place, publisher, year, edition, pages
2015. Vol. 17, no 26, 16886-16893 p.
IdentifiersURN: urn:nbn:se:kth:diva-170676DOI: 10.1039/c5cp00615eISI: 000356874000028PubMedID: 26060853ScopusID: 2-s2.0-84934344084OAI: oai:DiVA.org:kth-170676DiVA: diva2:840262
QC 201507072015-07-072015-07-032015-10-05Bibliographically approved