title: Dual binding modes of Congo red to amyloid protofibril surface observed in molecular dynamics simulations.
abstract: 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.
authors.affiliation: UC Davis Genome Center and Department of Applied Science, University of California, Davis, California 95616, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Wu
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Wang
authors.forename: Hongxing
authors.initials: H
authors.lastname: Lei
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Duan
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D001665:Binding Sites; D003198:Computer Simulation; D003224:Congo Red / Q000737:chemistry* / Q000494:pharmacology; D005656:Fungal Proteins / Q000737:chemistry* / Q000378:metabolism; D008968:Molecular Conformation; D011328:Prions / Q000737:chemistry* / Q000378:metabolism; D012997:Solvents / Q000737:chemistry; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D005656:Fungal Proteins; D011328:Prions; D012997:Solvents; D003224:Congo Red