Applications of density functional theory to iron-containing molecules of bioinorganic interest

Abstract

The past decades have seen an explosive growth in the application of density functional theory (DFT) methods to molecular systems that are of interest in a variety of scientific fields. Owing to its balanced accuracy and efficiency, DFT plays particularly useful roles in the theoretical investigation of large molecules. Even for biological molecules such as proteins, DFT finds application in the form of, e.g., hybrid quantum mechanics and molecular mechanics (QM/MM), in which DFT may be used as a QM method to describe a higher prioritized region in the system, while a MM force field may be used to describe remaining atoms. Iron-containing molecules are particularly important targets of DFT calculations. From the viewpoint of chemistry, this is mainly because iron is abundant on earth, iron plays powerful (and often enigmatic) roles in enzyme catalysis, and iron thus has the great potential for biomimetic catalysis of chemically difficult transformations. In this paper, we present a brief overview of several recent applications of DFT to iron-containing non-heme synthetic complexes, heme-type cytochrome P450 enzymes, and non-heme iron enzymes, all of which are of particular interest in the field of bioinorganic chemistry. Emphasis will be placed on our own work.

Keywords: QMMM; catalysis; density functional theory; enzyme reactions; iron-containing molecules; protein environment.

Scheme 1

Some of the (oxygen-bound) non-heme iron complexes studied by DFT calculations. L denotes atoms of non-oxygen ligands, but the use of the common symbol does not necessarily mean that the ligand atoms are equivalent.

Figure 1

(A) Five key d-type MOs of the TMC iron(IV)-oxo complex. (B) Typical electron-shift patterns for the reactions of non-heme iron(IV)-oxo complexes.

Scheme 2

(A) Iron(IV)-oxo formation from TMC Fe(II) and H₂O₂. (B) Cpd I formation in heme peroxidases. (C) The two pathways examined. Adapted from Hirao et al. (2011) with permission from the American Chemical Society.

Scheme 3

Schematic illustration of electron reorganization during the reactions in Scheme 2C. Adapted from Hirao et al. (2011) with permission from the American Chemical Society.

Figure 2

Energy profiles for the reactions in Scheme 2C in the presence (A) and absence (B) of 2,6-lutidine. Adapted from Hirao et al. (2011) with permission from the American Chemical Society.

Scheme 4

The three ligands studied by Myradalyyev et al. Reprinted from Myradalyyev et al. (2013) with permission from Elsevier.

Figure 3

(A) Relative stability of various complexes metal(II)-ligand complexes in different spin states. (B) Binding energy of the complexes. Adapted from Myradalyyev et al. (2013) with permission from Elsevier.

Figure 4

(A) Catalytic cycle of P450 (top) and a proposed mechanism of MBI caused by terminal acetylenes (bottom) (B) Energy diagrams (in kcal/mol) for the reactions of a ketene intermediate in the absence (A) and presence (B) of a water molecule. Adapted from Hirao et al. (2012) with permission from the American Chemical Society.

Scheme 5

Proposed mechanism of the MBI of P450 by UDMH. Adapted from Hirao et al. (2013a) with permission from Wiley-VCH.

Figure 5

(A) Reaction pathways considered for the MI formation from dimethylhydrazine. (B) Energy profiles (kcal/mol) for the four pathways considered. Adapted from Hirao et al. (2013a) with permission from the Wiley-VCH.

Scheme 6

Likely pathways of MIC formation starting from a tertiary amine (Hanson et al., 2010). Adapted from Hirao et al. (2013b).

Figure 6

DFT-calculated reaction energy profiles (in kcal/mol) for paths (A–D), which are initiated by H-abstraction from the O–H bond (A), H-abstraction from the N–H bond (B), N-oxidation (C), and H-abstraction from the methyl group (D). Reprinted from Hirao et al. (2013b).

Figure 7

Geometries of N-bound (A) and O-bound (B) forms of ¹MIC(II) and ²MIC(III), optimized at the M06/[SDD(Fe),6-31G^*(other)] level. Key distances are given in Å. The values below the geometries are relative energies (kcal/mol) obtained at the M06(SCRF)/6-311+G(d,p) level (¹MIC(II)/²MIC(III)), while the values in parentheses are relative energies obtained at the B3LYP(SCRF)/6-311+G(d,p) level. Reprinted from Hirao et al. (2013b).

Figure 8

(A) The resting state of the P450 catalytic cycle (B) Cpd I interacting with a water molecule. Reprinted from Thellamurege and Hirao (2013).

Figure 9

Active site of P450cam Cpd I. Reprinted from Hirao (2011a) with permission from the Chemical Society of Japan.

Figure 10

(A) E_es and E_vdW of each residue. (B) Key atomic spin populations calculated by ONIOM-ME and ONIOM-EE calculations. Adapted from Hirao (2011a) with permission from the Chemical Society of Japan.

Figure 11

Comparison of electrostatic energy contributions from amino acid residues 10-199 (A) and 200-414 and K⁺ (#415) (B), obtained in this work with method 1 (blue) and in a previous work (red). Reprinted from Thellamurege and Hirao (2014) with permission from the American Chemical Society.

Figure 12

Key Mulliken atomic spin populations obtained with ME-QM/MM (gas-phase), EE-QM/MM, and PE-QM/MM. Reprinted from Thellamurege and Hirao (2014) with permission from the American Chemical Society.

Scheme 7

MIOX-catalyzed conversion of myo-inositol into D-glucuronate. Reprinted from Hirao and Morokuma (2009) with permission from the American Chemical Society.

Scheme 8

O₂ Binding in MIOX to form a ferric-superoxide species. Reprinted from Hirao (2011b) with permission from the American Chemical Society.

Scheme 9

HEPD-catalyzed reactions of (A) 2-HEP and (B) 1-HEP. Reprinted from Hirao and Morokuma (2011b) with permission from the American Chemical Society.

Scheme 10

Theoretically proposed radical intermediate. Reprinted from Hirao and Morokuma (2011b) with permission from the American Chemical Society.

Figure 13

Energy profiles for the reactions of (A) 2-HEP and (B) 1-HEP, determined by ONIOM(DFT:MM) calculations. Reprinted from Hirao and Morokuma (2011b) with permission from the American Chemical Society.