NR AWSN
AU Wu,C.; Wang,Z.; Lei,H.; Zhang,W.; Duan,Y.
TI Dual binding modes of Congo red to amyloid protofibril surface observed in molecular dynamics simulations
QU Journal of the American Chemical Society 2007 Feb 7; 129(5): 1225-32
PT journal article; research support, n.i.h., extramural; research support, non-u.s. gov't
AB 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.
MH Amyloid/*chemistry/isolation & purification/metabolism; Amyloid beta-Protein/chemistry/isolation & purification/metabolism; Binding Sites; *Computer Simulation; Congo Red/*chemistry/pharmacology; Fungal Proteins/*chemistry/metabolism; Molecular Conformation; Prions/*chemistry/metabolism; Solvents/chemistry; Thermodynamics; Time Factors
AD UC Davis Genome Center and Department of Applied Science, University of California, Davis, California 95616, USA
SP englisch
PO USA