The Culprit Is in the Cave: The Core Sites Explain the Binding Profiles of Amyloid-Specific Tracers

Abstract

The design of molecular probes and tracer molecules with specificity toward amyloid beta (Aβ) fibrils is of paramount importance for the selective diagnosis of Alzheimer's disease. This requires a detailed understanding of the binding sites in amyloid targets, their number, and their binding mechanism for various tracer molecules. We adopt an integrated approach including molecular docking, molecular dynamics, and generalized Born-based free energy calculations to investigate site-specific interactions of different amyloid binding molecules. Our study reproduces the experimental results on the relative binding affinity of the tracers and amyloid binders and explains the feature of "multiple binding sites" in amyloid targets as probed by competition binding experiments. A major outcome of this study is that it is the core sites of the Aβ fibrils that are responsible for the experimentally reported binding profiles of tracers in amyloid targets rather than the surface sites that received much focus in earlier investigations.

Effect of Alzheimer Familial Chromosomal Mutations on the Amyloid Fibril Interaction with Different PET Tracers: Insight from Molecular Modeling Studies

“…In our previous studies we stressed the importance of the NMR conformation 8 of 2BEG where the phenyl alanine core have the most favourable interaction site. [24][25][26] The results from the residue-wise break up of the MM/GBSA contribution substantiate our earlier findings: In the case of florbetaben, in addition to the phenylalanine and valine, the leucine residues make a significant contribution towards a favourable interaction. We observe from the plot that for Iowa-AZD4694 there is a stronger interaction of the phenyl alanine and valine residues compared to the native system which may explain the exceptional nature of this mutation in that it has more favourable interaction energy than the native system.…”

“…[24][25][26] We therefore cross checked our result of these ambiguous systems using MD. The results for 17 nanosecond (ns) run are given in Table 2.…”

Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

“…The potency ranking of different cores with diverse electronic substitutions can only be achieved with QM calculation within systems displaying such complicated electronic variations participating in key interactions with the protein. The S1 site of Aβ 42 , the most amyloidogenic form of the peptide, was found to possess the highest binding affinity among the most possible sites for the styrylbenzoxazole derivatives from the QM calculation, which agrees with computational methods run in parallel and other experimental works . Binding free energy calculations (ie, an average over the ensemble binding energies) is another way to find the binding affinity .…”

“…The S1 site of Aβ 42 , the most amyloidogenic form of the peptide, was found to possess the highest binding affinity among the most possible sites for the styrylbenzoxazole derivatives from the QM calculation, 246 which agrees with computational methods run in parallel and other experimental works. 247,248 Binding free energy calculations (ie, an average over the ensemble binding energies) is another way to find the binding affinity. 249 Particularly, free energy perturbation (FEP) calculations was used in the design of novel spiroaminodihydropyrroles, 250 and acyl guanidine with a modified scaffold, 251 for inhibitors binding the P3 pocket of BACE1.…”

Gelatin grafted poly(D,L‐lactide) as an inhibitor of protein aggregation: An in vitro case study

“…Amyloid fibrils having sizes from microns to nano have been reported by various authors. [4,14,[30][31][32][35][36][37][38][39][40] Figure 1C shows the BSA fibrillation at different time point. After 4 hours, the molecules tried assembling in order and later, they aggregated together and forming the fibrils.…”