Quantum chemical insights into Alzheimer's disease: Curcumin's chelation with Cu(II), Zn(II), and Pd(II) as a mechanism for its prevention

Abstract

We provide quantum chemical insights into curcumin's prevention of Alzheimer' disease through curcumin's scavenging of neurotoxic Cu(II), Zn(II), and Pd(II) transition metal ions that catalyze polymerization of amyloid-b and promote misfolding of amyloid into neurotoxic conformations. We have employed high level quantum chemical computations to study the chelate complexes of curcumin with Cu(II), Zn(II), and Pd(II). Quantum chemically derived structures, IR spectra, and UV-visible spectra of these complexes corroborate with the observed spectra, confirming that the primary site of chelation is the bdiketone bridge through the loss of an enolic proton of curcumin. We have also obtained the various structural parameters such as the Mulliken charges on various centers, highest occupied, lowest unoccupied molecular orbitals-all of which confirm that curcumin forms chelate complexes and thus acts as a scavenger of these neurotoxic metal ions preventing Alzheimer's disease. We find that the open-d-shell Cu(II) and Pd(II) form nearly square planar complexes while the closed-d-shell Zn(II) forms a tetrahedral complex with curcumin.

Vibrational signatures of curcumin’s chelation in copper(II) complexes: An appraisal by IRMPD spectroscopy

“…Overall, the most stable complex Cu_1 with the likely contribution of low-lying rotamers Cu_2 and Cu_3, or kinetically trapped Cu_4 -Cu_7 rotamers where copper ion is bound to the O-atoms of curcumin deprotonated at the mid diketo functionality, well interprets the main IRMPD features of the bare [Cu(Cur − H)] + ion. Interestingly, these results confirm the metal coordination by the keto-enol moiety 4,15,20 and are consistent with previous evidence in condensed phase (in solid state and in different solvents) on mononuclear Cu(II)-curcumin complexes bearing acetate and water ligands where the involvement of phenolic OH group in metal complexation is excluded, 61 thus preserving the antioxidant property of Cur. The IRMPD spectrum of the [Cur + H] + ion is presented together with the calculated IR spectra of the lowest-lying diketo (HK_1) and keto-enol (HE_1) species for comparison purposes (Fig.…”

“…In addition, in a recent comparison between B3LYP and MP2, no significant differences in equilibrium geometries and relative energies regarding the closely related Zn(II)-curcumin complex were found. 61 This is expected since B3LYP has been shown to provide the same accuracy of MP2 in the determination of vibrational frequencies once a proper scaling factor is applied. 62 In addition, since the molecule is isolated, and given its bonding pattern, we expect dispersion corrections to play only a minor role.…”

“…While there is no guarantee that the global minimum will actually be identified, we note that good agreement is found with the curcumin geometries displayed earlier in the literature. [59][60][61] Several isomers, envisioned by varying the tautomeric form, either keto-enol or diketo, the site of (de)protonation and copper chelation, have originated sets of conformers differing for bond and torsional angles. In particular, curcumin allows rotation around C1 ′ -C1, C7-C1 ″ , C2-C3, and C5-C6 (but also C3-C4/C4-C5 in the neutral diketo form) bonds generating up to 24 rotational conformers.…”

Curcumin and Nano-Curcumin Mitigate Copper Neurotoxicity by Modulating Oxidative Stress, Inflammation, and Akt/GSK-3β Signaling

“…In addition to the findings of this study, Balasubramanian [ 68 , 69 ] presented important quantum chemical insights into the neuroprotective mechanism of CUR and its efficacy to prevent Alzheimer′s disease. The dual property of CUR to be nonpolar in parts and polar in other parts is due to the presence of both phenolic and enolic protons combined with an aliphatic hydrophobic bridge.…”

“…This property enables CUR to cross the blood–brain barrier (BBB) and bind to and prevent the polymerisation of amyloid-β (Aβ) oligomers [ 69 ]. By employing quantum chemical computations, Balasubramanian [ 68 ] studied the chelate complexes of CUR with Cu(II) and other transition metal ions that provoke the polymerisation of Aβ and formation of neurotoxic conformations, reporting that the β-diketone bridge, through the loss of an enolic proton of CUR, is the primary site of chelation. CUR can form stable chelate complexes at the β-diketone bridge, thereby scavenging neurotoxic metal ions and inhibiting Aβ polymerisation and the subsequent generation of neurotoxic conformations [ 68 ].…”