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

被引:154
作者
Wu, Chun
Wang, Zhixiang
Lei, Hongxing
Zhang, Wei
Duan, Yong [1 ]
机构
[1] Univ Calif Davis, Genome Ctr, Davis, CA 95616 USA
[2] Univ Calif Davis, Dept Appl Sci, Davis, CA 95616 USA
关键词
D O I
10.1021/ja0662772
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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 A beta 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.
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页码:1225 / 1232
页数:8
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共 71 条
[1]   Suppression by polycyclic compounds of the conversion of human amylin into insoluble amyloid [J].
Aitken, JF ;
Loomes, KM ;
Konarkowska, B ;
Cooper, GJS .
BIOCHEMICAL JOURNAL, 2003, 374 :779-784
[2]  
[Anonymous], MUENCHEN MED WOCHENS
[3]   Amyloid probes based on Congo Red distinguish between fibrils comprising different peptides [J].
Ashburn, TT ;
Han, H ;
McGuinness, BF ;
Lansbury, PT .
CHEMISTRY & BIOLOGY, 1996, 3 (05) :351-358
[4]   Amyloid fibril formation by Aβ16-22, a seven-residue fragment of the Alzheimer's β-amyloid peptide, and structural characterization by solid state NMR [J].
Balbach, JJ ;
Ishii, Y ;
Antzutkin, ON ;
Leapman, RD ;
Rizzo, NW ;
Dyda, F ;
Reed, J ;
Tycko, R .
BIOCHEMISTRY, 2000, 39 (45) :13748-13759
[5]   A WELL-BEHAVED ELECTROSTATIC POTENTIAL BASED METHOD USING CHARGE RESTRAINTS FOR DERIVING ATOMIC CHARGES - THE RESP MODEL [J].
BAYLY, CI ;
CIEPLAK, P ;
CORNELL, WD ;
KOLLMAN, PA .
JOURNAL OF PHYSICAL CHEMISTRY, 1993, 97 (40) :10269-10280
[6]   MOLECULAR-DYNAMICS WITH COUPLING TO AN EXTERNAL BATH [J].
BERENDSEN, HJC ;
POSTMA, JPM ;
VANGUNSTEREN, WF ;
DINOLA, A ;
HAAK, JR .
JOURNAL OF CHEMICAL PHYSICS, 1984, 81 (08) :3684-3690
[7]   Prefibrillar amyloid protein aggregates share common features of cytotoxicity [J].
Bucciantini, M ;
Calloni, G ;
Chiti, F ;
Formigli, L ;
Nosi, D ;
Dobson, CM ;
Stefani, M .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (30) :31374-31382
[8]   Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases [J].
Bucciantini, M ;
Giannoni, E ;
Chiti, F ;
Baroni, F ;
Formigli, L ;
Zurdo, JS ;
Taddei, N ;
Ramponi, G ;
Dobson, CM ;
Stefani, M .
NATURE, 2002, 416 (6880) :507-511
[9]   Affinity-based inhibition of β-amyloid toxicity [J].
Cairo, CW ;
Strzelec, A ;
Murphy, RM ;
Kiessling, LL .
BIOCHEMISTRY, 2002, 41 (27) :8620-8629
[10]   A model for structure-dependent binding of Congo red to Alzheimer β-amyloid fibrils [J].
Carter, DB ;
Chou, KC .
NEUROBIOLOGY OF AGING, 1998, 19 (01) :37-40