The Effect of Curcumin on the Stability of Aβ Dimers

Abstract

Aβ oligomers are potential targets for the diagnosis and therapy of Alzheimer's disease (AD). On the other hand, the molecule curcumin has been shown to possess significant therapeutic potential in many areas. In this paper, we use all-atom explicit solvent molecular dynamics simulations to study the effect of curcumin on the stability of Aβ amyloid protein oligomers. We observed that curcumin decreases the β-sheet secondary structural content within the Aβ oligomers without reducing the contacts between the monomers. The breaking of the β-sheet is found to be preceded by a deformation of the β-sheet structure due to hydrophobic interaction from the nearby curcumin. Furthermore, the π-stacking interaction between curcumin (keto ring and enol ring) and the aromatic residues of Aβ, which exists throughout the simulations, has also contributed to the diminishing of the β-sheet structure. Our analysis of the underwrapped amide-carbonyl hydrogen bonds reveals several stable dehydrons of the oligomer, especially the dehydron pair 34L and 41I, which curcumin tends to hover over. We have examined the paths of curcumin on the Aβ proteins and determined the common routes where curcumin lingers as it traverses around the Aβ. In consequence, our study has provided a detailed interaction picture between curcumin and the Aβ oligomers.

Curcumin Alters the Salt Bridge-containing Turn Region in Amyloid β(1–42) Aggregates

“…A␤ 42 Synthesis, Purification, and Sample Preparation-Synthesis and purification procedures of two different A␤ 42 peptide specimens with different 13 C and 15 N isotopic labeling schemes (P 1 and P 2 ) are described elsewhere (26). Purified A␤ 42 peptides were initially dissolved in pH 11.0 water (adjusted by NaOH) to prepare 2 mM stock solutions.…”

“…Cross-polarization to 13 C and 15 N from 1 H was implemented using a linear ramped radio frequency field (27) centered around 65 kHz on the 1 H channel and with a 55-kHz field on the 13 C/ 15 N channel with a contact time between 2.5 and 4.0 ms. 1 H dipolar decoupling was accomplished using the swept frequency two-pulse phase modulation ( ϭ 10°) decoupling scheme (28) with a field strength of 85 kHz. Two-dimensional 13 C-13 C through-space NMR spectra were recorded using second-order dipolar recoupling schemes of PARIS-xy (m ϭ 1, n ϭ 2) (29) and PDSD (30) and mixing periods of 100 and 1000 ms, respectively. 1 H irradiation of 15 kHz was used while applying PARIS-xy (m ϭ 1, n ϭ 2).…”

“…The number of scans per free induction decay and interscan delay was fixed to 256 and 2 s, and 512 and 1.5 s in case of PARIS-xy (m ϭ 1, n ϭ 2) and PDSD, respectively. Frequencyselective 13 C-15 N rotational-echo double-resonance (REDOR) experiments were recorded using the pulse sequence designed by Jaroniec et al (31). Rotor-synchronized trains of phase-alternated pulses following xy-8 scheme (32) were applied on the 15 N channel.…”

“…Rotor-synchronized trains of phase-alternated pulses following xy-8 scheme (32) were applied on the 15 N channel. 466.7 s long frequency-selective Gaussian pulses were applied at the 13 C␥ and 15 N frequencies of Asp-23 and Lys-28, respectively, in the middle of the REDOR-dephasing period ( mix ). Reference spectra (S 0 ) were recorded after removing the frequency-selective refocusing pulse on 15 …”

“…Curcumin is known to bind to ␤-sheet-rich A␤ species like protofibrils and fibrils and not to unstructured monomers (7). Theoretical studies have suggested that curcumin can interact with A␤ oligomers to disrupt the ␤-sheet content and possibly alter the conformation of several regions of the A␤ molecule (13). Experimental studies using curcumin analogues with different linker lengths have shown that there is an optimum linker length that interacts with A␤, suggesting that the interaction of A␤ with curcumin is site-specific (14,15).…”