Dual binding modes of Congo red to amyloid protofibril surface observed in molecular dynamics simulations.

Dual binding modes of Congo red to amyloid protofibril surface observed in molecular dynamics simulations. Research Abstract Details 

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Dual binding modes of Congo red to amyloid protofibril surface observed in molecular dynamics simulations. Abstract Text:

Chun Wu,Zhixiang Wang,Hongxing Lei,Wei Zhang,Yong Duan,

Congo red has been used to identify amyloid fibrils in tissues for more than 80 years and is also a weak inhibitor to both amyloid-beta fibril formation and toxicity. However, the specificity of the binding and its inhibition mechanism remain unclear. Using all-atom molecular dynamics simulations with the explicit solvent model, we have identified and characterized two specific binding modes of Congo red molecules to a protofibril formed by an amyloidogenic fragment (GNNQQNY) of the yeast prion protein Sup35. The observation of dual-mode was consistent with the experimentally observed dual-mode binding to Abeta fibrils by a series of compounds similar to Congo red. In the primary mode, Congo red bound to a regular groove formed by the first three residues (GNN) of the beta-strands along the beta-sheet extension direction. Comparative simulations demonstrated that Thioflavin T also bound to the grooves on KLVFFAE protofibril surface. Because of the ubiquitous long grooves on the amyloid fibril surface, we propose that this binding interaction could be a general recognition mode of amyloid fibrils by Congo red, Thioflavin T, and other long flat molecules. In the secondary mode, Congo red bound parallel to the beta-strands on the edge or in the middle of a beta-sheet. The primary binding mode of Congo red and GNNQQNY protofibril was more stable than the secondary mode by -5.7 kcal/mol as estimated by the MM-GBSA method. Detailed analysis suggests that the hydrophobic interactions play important roles for burial of the hydrophobic part of the Congo red molecules. Two potential inhibition mechanisms of disrupting beta-sheet stacking were inferred from the primary mode, which could be exploited for the development of non-peptidic amyloid-specific inhibitors.

Dual binding modes of Congo red to amyloid protofibril surface observed in molecular dynamics simulations. Publishing Authors By Initials

C Wu,Z Wang,H Lei,W Zhang,Y Duan,

For similar natural sciences: time: time factors research abstracts see: natural sciences: time: time factors research

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Dual binding modes of Congo red to amyloid protofibril surface observed in molecular dynamics simulations. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Journal of the American Chemical Society

VOLUME: 129

Page Numbers: 1225-32

Journal Abbreviation: J. Am. Chem. Soc.

ISSN: 0002-7863

DAY: 7

MONTH: Feb

YEAR: 2007

Dual binding modes of Congo red to amyloid protofibril surface observed in molecular dynamics simulations. Information

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LANGUAGE: eng

NlmUniqueID: 7503056

Dual binding modes of Congo red to amyloid protofibril surface observed in molecular dynamics simulations. Keywords Mesh Terms:

KEYWORDS: Time Factors

MESH TERMS: chemistry

Chemical & Substance for Abstract: Dual binding modes of Congo red to amyloid protofibril surface observed in molecular dynamics simulations. Information

Substance Name: Congo Red

Registry Number: 573-58-0

Grant and Affiliation Information for Dual binding modes of Congo red to amyloid protofibril surface observed in molecular dynamics simulations.

AFFILIATION: UC Davis Genome Center and Department of Applied Science, University of California, Davis, California 95616, USA.

Country: United States

AGENCY: United States NIGMS

GRANT: GM67168

ACRONYM: GM

MEDLINETA: J Am Chem Soc

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