Curcumin binding to beta amyloid: a computational study

PPN Rao, T Mohamed, K Teckwani… - Chemical biology & drug …, 2015 - Wiley Online Library
PPN Rao, T Mohamed, K Teckwani, G Tin
Chemical biology & drug design, 2015Wiley Online Library
Curcumin, a chemical constituent present in the spice turmeric, is known to prevent the
aggregation of amyloid peptide implicated in the pathophysiology of Alzheimer's disease.
While curcumin is known to bind directly to various amyloid aggregates, no systematic
investigations have been carried out to understand its ability to bind to the amyloid
aggregates including oligomers and fibrils. In this study, we constructed computational
models of (i) Aβ hexapeptide 16 KLVFFA 21 octamer steric‐zipper β‐sheet assembly and (ii) …
Curcumin, a chemical constituent present in the spice turmeric, is known to prevent the aggregation of amyloid peptide implicated in the pathophysiology of Alzheimer's disease. While curcumin is known to bind directly to various amyloid aggregates, no systematic investigations have been carried out to understand its ability to bind to the amyloid aggregates including oligomers and fibrils. In this study, we constructed computational models of (i) Aβ hexapeptide 16KLVFFA21 octamer steric‐zipper β‐sheet assembly and (ii) full‐length Aβ fibril β‐sheet assembly. Curcumin binding in these models was evaluated by molecular docking and molecular dynamics (MD) simulation studies. In both the models, curcumin was oriented in a linear extended conformation parallel to fiber axis and exhibited better stability in the Aβ hexapeptide 16KLVFFA21 octamer steric‐zipper model (Ebinding = −10.05 kcal/mol) compared to full‐length Aβ fibril model (Ebinding = −3.47 kcal/mol). Analysis of MD trajectories of curcumin bound to full‐length Aβ fibril shows good stability with minimum Cα‐atom RMSD shifts. Interestingly, curcumin binding led to marked fluctuations in the 14HQKLVFFA21 region that constitute the fibril spine with RMSF values ranging from 1.4 to 3.6 Ĺ. These results show that curcumin binding to Aβ shifts the equilibrium in the aggregation pathway by promoting the formation of non‐toxic aggregates.
Wiley Online Library