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Insights into enzymatic halogenation from computational studies.

Senn HM - Front Chem (2014)

Bottom Line: This Review summarizes the main insights gained from these studies.It also seeks to identify open questions that are amenable to computational investigations.The studies discussed herein serve to illustrate some of the limitations of the current computational approaches and the challenges encountered in computational mechanistic enzymology.

View Article: PubMed Central - PubMed

Affiliation: WestCHEM School of Chemistry, University of Glasgow Glasgow, UK.

ABSTRACT
The halogenases are a group of enzymes that have only come to the fore over the last 10 years thanks to the discovery and characterization of several novel representatives. They have revealed the fascinating variety of distinct chemical mechanisms that nature utilizes to activate halogens and introduce them into organic substrates. Computational studies using a range of approaches have already elucidated many details of the mechanisms of these enzymes, often in synergistic combination with experiment. This Review summarizes the main insights gained from these studies. It also seeks to identify open questions that are amenable to computational investigations. The studies discussed herein serve to illustrate some of the limitations of the current computational approaches and the challenges encountered in computational mechanistic enzymology.

No MeSH data available.


Hydrogen abstraction pathways for 5[FeIV =O] isomers D3 and D4. In the σ-pathway, an electron from the C–H bond is accepted into the σ*(Fe=O) orbital, hence an attack angle of 180° is ideal. In the π-pathway, the acceptor orbital is a π*(Fe=O), so the ideal attack angle is around 120°.
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Figure 8: Hydrogen abstraction pathways for 5[FeIV =O] isomers D3 and D4. In the σ-pathway, an electron from the C–H bond is accepted into the σ*(Fe=O) orbital, hence an attack angle of 180° is ideal. In the π-pathway, the acceptor orbital is a π*(Fe=O), so the ideal attack angle is around 120°.

Mentions: The difference in reactivity toward hydrogen abstraction between the [FeIV =O] isomers D3 and D4, or more generally, between a linear vs. side-ways attack of the C–H bond on the Fe=O unit, has been studied in detail for various small [FeIV =O] complexes (Chen et al., 2010a; Geng et al., 2010; Janardanan et al., 2010; Ye and Neese, 2011) using B3LYP and CCSD(T) methods. In brief, the actual reactive form, which evolves as the Fe=O bond is slightly stretched as the transition state is approached, is best described as [FeIII−O•]. On the quintet surface, the spatial orientation of the reactive orbitals in 5[FeIII−O•] favor a linear attack (σ-pathway) over a side-ways attack (π-pathway); see Figure 8. The preference is reversed on the triplet surface. In the active site of an enzyme, the relative position and orientation of the reactive Fe=O and C–H bonds are restrained by the protein environment. The attack pathway is therefore controlled, or at least strongly influenced, by steric requirements, rather than intrinsic electronic preferences. Moreover, the coordination geometry and ligand environment of the iron center, which are also influenced by the protein, determine whether the most favorable acceptor orbital in any given spin state is of σ- or π-character. QM/MM studies on the NHFe/2-OG hydroxylase AlkB (Fang et al., 2013; Quesne et al., 2014), taking into account the full protein environment, indeed found attack pathways for C–H abstraction that deviated sometimes substantially from an ideal σ- or π-attack geometry.


Insights into enzymatic halogenation from computational studies.

Senn HM - Front Chem (2014)

Hydrogen abstraction pathways for 5[FeIV =O] isomers D3 and D4. In the σ-pathway, an electron from the C–H bond is accepted into the σ*(Fe=O) orbital, hence an attack angle of 180° is ideal. In the π-pathway, the acceptor orbital is a π*(Fe=O), so the ideal attack angle is around 120°.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4227530&req=5

Figure 8: Hydrogen abstraction pathways for 5[FeIV =O] isomers D3 and D4. In the σ-pathway, an electron from the C–H bond is accepted into the σ*(Fe=O) orbital, hence an attack angle of 180° is ideal. In the π-pathway, the acceptor orbital is a π*(Fe=O), so the ideal attack angle is around 120°.
Mentions: The difference in reactivity toward hydrogen abstraction between the [FeIV =O] isomers D3 and D4, or more generally, between a linear vs. side-ways attack of the C–H bond on the Fe=O unit, has been studied in detail for various small [FeIV =O] complexes (Chen et al., 2010a; Geng et al., 2010; Janardanan et al., 2010; Ye and Neese, 2011) using B3LYP and CCSD(T) methods. In brief, the actual reactive form, which evolves as the Fe=O bond is slightly stretched as the transition state is approached, is best described as [FeIII−O•]. On the quintet surface, the spatial orientation of the reactive orbitals in 5[FeIII−O•] favor a linear attack (σ-pathway) over a side-ways attack (π-pathway); see Figure 8. The preference is reversed on the triplet surface. In the active site of an enzyme, the relative position and orientation of the reactive Fe=O and C–H bonds are restrained by the protein environment. The attack pathway is therefore controlled, or at least strongly influenced, by steric requirements, rather than intrinsic electronic preferences. Moreover, the coordination geometry and ligand environment of the iron center, which are also influenced by the protein, determine whether the most favorable acceptor orbital in any given spin state is of σ- or π-character. QM/MM studies on the NHFe/2-OG hydroxylase AlkB (Fang et al., 2013; Quesne et al., 2014), taking into account the full protein environment, indeed found attack pathways for C–H abstraction that deviated sometimes substantially from an ideal σ- or π-attack geometry.

Bottom Line: This Review summarizes the main insights gained from these studies.It also seeks to identify open questions that are amenable to computational investigations.The studies discussed herein serve to illustrate some of the limitations of the current computational approaches and the challenges encountered in computational mechanistic enzymology.

View Article: PubMed Central - PubMed

Affiliation: WestCHEM School of Chemistry, University of Glasgow Glasgow, UK.

ABSTRACT
The halogenases are a group of enzymes that have only come to the fore over the last 10 years thanks to the discovery and characterization of several novel representatives. They have revealed the fascinating variety of distinct chemical mechanisms that nature utilizes to activate halogens and introduce them into organic substrates. Computational studies using a range of approaches have already elucidated many details of the mechanisms of these enzymes, often in synergistic combination with experiment. This Review summarizes the main insights gained from these studies. It also seeks to identify open questions that are amenable to computational investigations. The studies discussed herein serve to illustrate some of the limitations of the current computational approaches and the challenges encountered in computational mechanistic enzymology.

No MeSH data available.