Binding of Thioflavin T and Related Probes to Polymorphic Models of Amyloid-β Fibrils

Abstract

Alzheimer's disease is a challenge of the utmost importance for contemporary society. An early diagnosis is essential for the development of treatments and for establishing a network of support for the patient. In this light, the deposition in the brain of amyloid-β fibrillar aggregates, which is a distinctive feature of Alzheimer, is key for an early detection of this disease. In this work we propose an atomistic study of the interaction of amyloid tracers with recently published polymorphic models of amyloid-β 1-40 and 1-42 fibrils, highlighting the relationship between marker architectures and binding affinity. This work uncovers the importance of quaternary structure, and in particular of junctions between amyloid-β protofilaments, as the key areas for marker binding.

Synthesis, crystal structure studies and solvatochromic behaviour of two 2-{5-[4-(dimethylamino)phenyl]penta-2,4-dien-1-ylidene}malononitrile derivatives

“…The optical and biological properties of NIR probes for the identification of -amyloids have been evaluated experimentally by different research groups (Zhou et al, 2017;Peccati et al, 2016;Kim et al, 2015;Cui, 2014;Peccati et al, 2017;Murugan et al, 2014). Fluorescent-based and multi-photon microscopy-based imaging techniques were used for -amyloid identification.…”

Rhenium Complexes of Bis(benzothiazole)‐Based Tetraarylethylenes as Selective Luminescent Probes for Amyloid Fibrils

“…Bis(thiophene) derivative NIAD‐4 ( 2 ) (Figure ) has emerged as a promising alternative to ThT owing to its improved optical properties (λ em >600 nm) and ability to cross the blood–brain barrier as a neutral compound . Recent molecular dynamics simulations indicate that both NIAD‐4 and ThT interact preferentially at the junction between protofilaments of Aβ 42 fibrils by embedding in a binding pocket with a channel‐like geometry that matches their common linear/rod‐like architectures . A series of luminescent conjugated oligothiophenes (LCOs, e.g., 3 ) also has been introduced as sensitive probes for protein aggregates…”

“…[13] Recent molecular dynamics simulations indicate that both NIAD-4 and ThT interactp referentiallya tt he junction between protofilaments of Ab 42 fibrils by embeddingi nabinding pocket with ac hannel-like geometry that matches their commonlinear/rod-like architectures. [14] Aseries of luminescent conjugated oligothiophenes (LCOs, e.g., 3)a lso has been introduced as sensitiveprobes forprotein aggregates. [15] Recently,s everal photoluminescent Re I ,R u II and cyclometalated Ir III complexes featuring large planar poly-(pyridyl) ligands have been investigated for their ability to detect amyloid fibrils.…”

Computational Insight into the Effect of Natural Compounds on the Destabilization of Preformed Amyloid-β(1-40) Fibrils

“…Atomistic computer simulations are well suited to provide molecular-level details of amyloid oligomer and fibril interactions with ligands, helping in the future development and characterization of druggable modalities [12]. Basically four aspects of the flavonoids-amyloid interaction have been studied by computational methods: 1) the effect of ligands on the conformational transitions of Aβ monomers from initial random coil or α-helix into β-sheet structures [13,14] and ligand-mediated conformational change on Aβ dimer [15] by means of Replica Exchange Molecular Dynamics (REMD) simulations; 2) the effect of ligands on the aggregation of Aβ (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36) using Coarse-Grained 2 of 15 Simulations [16]; 3) effect of ligands on the conformation and stability of amyloid-beta mutants [17] by Molecular Dynamics (MD) simulations; 4) preferential binding sites of ligands and their effect on amyloid structure-dynamics [18] on Aβ fragments and full-length single Aβ protofilament [19][20][21][22][23][24][25] by means of Docking experiments, MD simulations and Free Energy calculations.…”

“…Although recently a few studies devoted their attention to the interaction of ligands (mainly markers for amyloid detection ref. [26][27][28]) with multiple Aβ protofilaments, to the best of our knowledge this aspect has not been investigated thoroughly for natural polyphenol ligands, except for curcumin [19].…”