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First-Principles Study of the Dispersion Effects in the Structures and Keto-Enol Tautomerization of Curcumin.

ABSTRACT: Noncovalent interactions, such as dispersion, play a significant role in the stability of flexible molecules, such as curcumin. This study revealed the importance of dispersion correction in the structure and keto-enol tautomerization of curcumin, which has rarely been addressed in computational studies. We rigorously constructed all possible unique curcumin conformers in the enol and keto forms within the first-principles framework. Regardless of the different environments, we carefully explained the agreement between the computational geometry (in the gas phase) and the experimental measurement (in the polymorph) by using dispersion correction. The calculation results for the aqueous solution of conformational abundance, thermochemistry, and reaction kinetics support the experimental observations after considering the dispersion correction. The study also suggests a water-catalyzed mechanism for keto-enol tautomerization, where dispersion correction plays a role in decreasing the energy barrier and making the keto form thermochemically and kinetically favorable. Our results could be helpful in future computational studies to find a method for increasing the aqueous solubility of curcumin; hence, the potential of curcumin as a multifunctional medicine can be fully achieved.

SUBMITTER: Madinah R

PROVIDER: S-EPMC10515353 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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First-Principles Study of the Dispersion Effects in the Structures and Keto-Enol Tautomerization of Curcumin.

Madinah Roichatul R Rusydi Febdian F Fadilla Rizka N RN Khoirunisa Vera V Boli Lusia S P LSP Saputro Adhitya G AG Hassan Nur H NH Ahmad Azizan A

ACS omega 20230901 37

Noncovalent interactions, such as dispersion, play a significant role in the stability of flexible molecules, such as curcumin. This study revealed the importance of dispersion correction in the structure and keto-enol tautomerization of curcumin, which has rarely been addressed in computational studies. We rigorously constructed all possible unique curcumin conformers in the enol and keto forms within the first-principles framework. Regardless of the different environments, we carefully explain ...[more]

PMID: 37744805

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Project description:The mechanism of acid-catalyzed keto-enol tautomerization of β-cyclopentanedione (CPD) in solution is studied computationally. Reaction profiles are first calculated for a limited solvation environment using ab initio and density functional methods. Barrier heights for systems including up to one hydration shell of explicit water molecules depend strongly on the number of waters involved in proton transfer and to a lesser but significant extent on the number of waters forming hydrogen bonds with waters in the proton-transfer chain (each such water reduces the barrier by 4.4 kcal/mol on average). Barriers of 8-13 kcal/mol were obtained when a full or nearly full hydration shell was present, consistent with calculations for nonacid-catalyzed keto-enol tautomerization of related molecules. The presence of HOCl reduced the barrier by 4.5 kcal/mol in relation to the gas phase, consistent with the well-known principle that keto-enol tautomerization can be acid- or base-catalyzed. The reaction was also modeled beginning with snapshots of reactant conformations taken from a 300 K molecular dynamics simulation of CPD, HOCl, and 324 explicit waters. Reaction profiles were calculated at a QM/MM level with waters in the first hydration shell either fixed or energy-minimized at each step along the reaction coordinate. A substantial variation in barrier height was observed in both cases, depending primarily on electrostatic interactions (hydrogen bonding) with first-hydration-shell waters and, to a lesser extent, on electrostatic interactions with more distant waters and geometric distortion effects. For the lowest barriers, the extent of barrier reduction by waters involved in proton transfer is consistent with the limited solvation results, but further barrier reduction due to hydrogen bonding to waters involved in proton transfer is not observed. It is postulated that this is because highly flexible structures such as extensive hydrogen bonding networks optimal for reaction are entropically disfavored and so may not contribute significantly to the observed reaction rate.

Project description:We have explored the effect of ring size on keto-enol tautomerization of α- and β-cyclodiones using the M062X-SMDaq/6-31+G(d,p)//M062X/6-31+G(d,p) level of theory. The calculated results show that the activation free energy barrier for the keto-enol tautomerization process of α-cyclopropanedione (1) is 54.9 kcal/mol, which is lower compared to that of the other cyclic diketo systems studied here. The four-membered α- and β-cyclobutanedione (2 and 6) do not favor keto-enol tautomerization unlike other studied cyclic systems because of the ring strain developed in the transition-state geometries and their corresponding products. Water-assisted keto-enol tautomerization with one molecule reveals that the free energy activation barriers reduce almost half compared to those for the uncatalyzed systems. The two-water-assisted process is favorable as the activation free energy barriers lowered by ∼10 kcal/mol compared to those of the one-water-assisted process. The ion-pair formation seems to govern the lowering of activation barriers of α- and β-cyclodiones with two water molecules during the keto-enol tautomerization process, which however also overcomes the favorable aromatization in the three-membered ring system. The free energy activation barriers calculated with the M062X-SMDaq/6-31+G(d,p) level predicted that the keto-enol tautomerization process for the α-cyclodiones follows the following trend: 2 > 3 > 4 > 5 > 1. Water-assisted tautomerization of α-cyclodiones also predicted 1-W and 1-2W as the most favored processes; however, 5-W and 5-2W were found to be disfavored in this case. The β-cyclodione systems also showed similar trends as obtained with α-diketone systems. The influence of bulk solvent on the keto-enol tautomerization process favors the formation of the enol form in a more polar solvent medium even under mixed solvent conditions in acetonitrile and hexane at M062X-SMDacetonitrile/6-31+G(d,p) and M062X-SMDhexane/6-31+G(d,p) levels of theory.

Dataset Information

First-Principles Study of the Dispersion Effects in the Structures and Keto-Enol Tautomerization of Curcumin.

Publications

First-Principles Study of the Dispersion Effects in the Structures and Keto-Enol Tautomerization of Curcumin.

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