Quantum chemistry-based verification of antioxidative action of iodide in mitochondria

Background: In view of the well-known health-care qualities of aqueous potassium iodide (KI), quantum chemistry-based molecular modeling, i.e., density functional theory-based molecular modeling (DFT/MM) is undertaken to understand how iodide ion (I-) shows antioxidative properties on aqueous phosphorylation process in mitochondria (mt) of alive cells. Materials and methods: We perform DFT/MM equivalent to the quantum mechanics/molecular mechanics (QM/MM) method, by using the B3LYP exchangecorrelation function and the 6–31G(d) basis set with Spartan’18 (Wavefunction, Inc. Irvine, CA). Results: Iodide ion (I-) is in equilibrium with hydrogen iodide (HI), being oxidized to hypoiodous acid (HOI) by ground state oxygen (O2) or by hydrogen peroxide (HOOH) in aqueous systems. DFT/MM also verifies that van der Waals force (vdW) induces van der Waal (vdW) aggregation of hypoiodous acid (HOI) with phenylalanine, resulting in giving tyrosine, and that vdW works strongly on aggregation of tyrosine with HOI, leading to formation of 2,6-diiodotyrosine via 2-iodotyrosine. 2,6-Diiodotyrosine as homolog of thyroid hormones T4 is validated to show antioxidative action to evil active oxygen in mt, i.e., HOOH and hydroxyl radical.


Introduction
Iodine has long been known to be an essential trace element for disease-free life and longevity. Recent open access review articles and website documents on iodine mention that iodine as an elemental component of thyroid hormones is required at all stages of life especially during growth period [1,2]. In other words, thyroid hormones, i.e., tetraiodothyronine (T4 or thyroxine) and triiodothyronine (T3) are recognized to play an important role in general growth and development of the body cells along with metabolic power producing processes in mt as powerhouse of cells. Our preceding molecular modeling (DFT/MM) studies validated that antioxidative action of thyroid hormone of T3 and T4 work as superoxide dismutase (SOD) in reductive phosphorylation processes in mitochondria (mt) [3]. These scientific facts predict that the quality and number of active mt is important to sustain the daily functions of mt in cells of healthy human body and then element iodide ion (I -) is speculated to be vital for formation of iodine-containing chemicals like T3 and T4 in aqueous cells or in mt systems. Biological and chemical processes starting from iodide ion (I -) and phenylalanine and ending in formation of the iodinated tyrosine derivatives will be analyzed, verified and predicted by DFT/MM using software of Spartan' 18 installed in a PC.

Verification of hydrogen iodide in equilibrium with iodide ion (I -) in aqueous systems
We speculated that salt of potassium iodide (K + I -) must be in equilibrium with hydrogen iodide H + Iand covalent bonding H-I in aqueous system. As shown in Figure 1 and  2 are speculated to be in equilibrium with each other in aqueous systems like blood streams ( Figure 1).

Verification of formation of hypoiodous acid (IOH) from hydrogen iodide in aqueous blood systems
In aqueous blood systems, ground state oxygen (    Quantum chemistry considerations of LUMO in highly reactive electrophilic I + and HOMO of phenylalanine is examined. During reacting interactions between LUMO's and HOMO's, the electrophile I + is allow to position itself on an electron rich para-position, at a perpendicular distance of 1.6 Å, and then molecular modeled. The resulting EQG of I + &phenylalanine is shown in Figure 4 and Table S4. The EQG reveals that I + positions itself at a distance of 2.261Å, the C-H bond on position 4 elongates to 1.093 Å, and the C-H bonding angle to the face of phenylalanine ring is 114.45°. In addition, the structure of phenylalanine of which para-position both carbon I + and HOare located at each vertical distance of 1.6 Å is also molecular modeled (Figure 4 and Table S4). The change in bonding distance and the C-H bonding angle at para-position are all comparable to those of EQG of I + &Phenylalanine. EQG of I + &phenylalanine&HOlooks like transition state to tyrosine via effective aggregation of phenylamine with IOH.

Verification of IOH-induced iodination of tyrosine to 2,6-diiodotyrosine as homologues of thyroid hormones, T4
An aggregate of tyrosine with I + &HO -&H 2 O is optimized by MMFF operation on Spartan'18 and then molecular modeled as summarized in Figure 5 and Table S5. The resulting EQG structure indicates that the nonbonding distance between I + and the ortho carbon (2,259Å) is shorter, and the bonding distance (1.866Å) of ring HO group elongates, and the bond angle (147.23°) of HO at ortho-position to phenyl ring is out of plane, and the bond distance (1.088Å) of H-O elongates.
The EQG analysis is true for formation of 2,6-diiodotyrosine from 2-iodotyrosine as shown in Figure 5 and Table S5. It is worth noting that both heats of formation, ΔE=-250 kcal/mol, ΔE=-361 kcal/mol is negative and large and 2,6-diodotyrosine is predicted to be produced in more quantities than 2-iodotyrosine as the amount of T4 (reference interval 8~17 pg/mL) is greater than that of T3 (reference interval 2.1~3.1 pg/mL) in the blood stream.