structure and dynamics of amyloid-β segmental polymorphisms的结构和动力学amyloid-β节段多态性.pdfVIP

Structure and Dynamics of Amyloid-b Segmental Polymorphisms Workalemahu M. Berhanu, Ulrich H. E. Hansmann* Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma, United States of America Abstract It is believed that amyloid-beta (Ab) aggregates play a role in the pathogenesis of Alzheimer’s disease. Ab molecules form b- sheet structures with multiple interaction sites. This polymorphism gives rise to differences in morphology, physico- chemical property and level of cellular toxicity. We have investigated the conformational stability of various segmental polymorphisms using molecular dynamics simulations and find that the segmental polymorphic models of Ab retain a U- shaped architecture. Our results demonstrate the importance of inter-sheet side chain-side chain contacts, hydrophobic contacts among the strands (b1 and b2) and of salt bridges in stabilizing the aggregates. Residues in b-sheet regions have smaller fluctuation while those at the edge and loop region are more mobile. The inter-peptide salt bridges between Asp23 and Lys28 are strong compared to intra-chain salt bridge and there is an exchange of the inter-chain salt-bridge with intra- chain salt bridge. As our results suggest that Ab exists under physiological conditions as an ensemble of distinct segmental polymorphs, it may be necessary to account in the development of therapeutics for Alzheimer’s disease the differences in structural stability and aggregation behavior of the various Ab polymorphic forms. Citation: Berhanu WM, Hansmann UHE (2012) Structure and Dynamics of Amyloid-b Segmental Polymorphisms. PLoS ONE 7(7): e41479. doi:10.1371/ journal.pone.0041479 Editor: Jie Zheng, University of Akron, United States of America Received May 2, 2012; Accepted June 21, 2012; Published July 24, 2012 Copyright: 2012 Berhanu