Dual Binding Modes of Congo Red to Amyloid Protofibril Surface Observed in Molecular Dynamics Simulations
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- 作者：Chun Wu ; Zhixiang Wang ; Hongxing Lei ; Wei Zhang ; Yong Duan
- 刊名：Journal of the American Chemical Society
- 出版年：2007
- 出版时间：February 7, 2007
- 年：2007
- 卷：129
- 期：5
- 页码：1225 - 1232
- 全文大小：337K
- 年卷期：v.129,no.5(February 7, 2007)
- ISSN：1520-5126
文摘
Congo red has been used to identify amyloid fibrils in tissues for more than 80 years and is alsoa weak inhibitor to both amyloid-
fibril formation and toxicity. However, the specificity of the binding andits inhibition mechanism remain unclear. Using all-atom molecular dynamics simulations with the explicitsolvent model, we have identified and characterized two specific binding modes of Congo red moleculesto a protofibril formed by an amyloidogenic fragment (GNNQQNY) of the yeast prion protein Sup35. Theobservation of dual-mode was consistent with the experimentally observed dual-mode binding to A fibrilsby a series of compounds similar to Congo red. In the primary mode, Congo red bound to a regular grooveformed by the first three residues (GNN) of the -strands along the -sheet extension direction. Comparativesimulations 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 interactioncould be a general recognition mode of amyloid fibrils by Congo red, Thioflavin T, and other long flatmolecules. In the secondary mode, Congo red bound parallel to the -strands on the edge or in the middleof a -sheet. The primary binding mode of Congo red and GNNQQNY protofibril was more stable than thesecondary mode by -5.7 kcal/mol as estimated by the MM-GBSA method. Detailed analysis suggeststhat the hydrophobic interactions play important roles for burial of the hydrophobic part of the Congo redmolecules. Two potential inhibition mechanisms of disrupting -sheet stacking were inferred from the primarymode, which could be exploited for the development of non-peptidic amyloid-specific inhibitors.
fibril formation and toxicity. However, the specificity of the binding andits inhibition mechanism remain unclear. Using all-atom molecular dynamics simulations with the explicitsolvent model, we have identified and characterized two specific binding modes of Congo red moleculesto a protofibril formed by an amyloidogenic fragment (GNNQQNY) of the yeast prion protein Sup35. Theobservation of dual-mode was consistent with the experimentally observed dual-mode binding to A fibrilsby a series of compounds similar to Congo red. In the primary mode, Congo red bound to a regular grooveformed by the first three residues (GNN) of the -strands along the -sheet extension direction. Comparativesimulations 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 interactioncould be a general recognition mode of amyloid fibrils by Congo red, Thioflavin T, and other long flatmolecules. In the secondary mode, Congo red bound parallel to the -strands on the edge or in the middleof a -sheet. The primary binding mode of Congo red and GNNQQNY protofibril was more stable than thesecondary mode by -5.7 kcal/mol as estimated by the MM-GBSA method. Detailed analysis suggeststhat the hydrophobic interactions play important roles for burial of the hydrophobic part of the Congo redmolecules. Two potential inhibition mechanisms of disrupting -sheet stacking were inferred from the primarymode, which could be exploited for the development of non-peptidic amyloid-specific inhibitors.