Charge Density in Enzyme Active Site as a Descriptor of Electrostatic Preorganization

Fuller, Jack T.; Wilson, Timothy; Eberhart, Mark E.; Alexandrova, Anastassia N.

doi:10.1021/acs.jcim.8b00958

Cited by 44 publications

(98 citation statements)

References 52 publications

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“… 13 Recent independent analysis using quantum theory of atoms in molecules (QTAIM) reported a significant correlation between charge density, external electric field, and activation energy changes in KSI. 29 These results obtained by entirely different methodologies are complementary with ours reinforcing conclusions in both studies. This is in line with the well-known proton-coupled electron-transfer effects.…”

Section: Resultssupporting

confidence: 85%

Extreme Catalytic Power of Ketosteroid Isomerase Related to the Reversal of Proton Dislocations in Hydrogen-Bond Network

2020

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Dynamic electrostatic catalytic field (DECF) vectors derived from transition state and reactant wavefunctions for the two-step reaction occurring within ketosteroid isomerase (KSI) have been calculated using MP2/aug-cc-pVTZ and lower theory levels to determine the magnitude of the catalytic effect and the optimal directions of proton transfers in the KSI hydrogen-bond network. The most surprising and meaningful finding is that the KSI catalytic activity is enhanced by proton dislocations proceeding in opposite directions for each of the two consecutive reaction steps in the same hydrogen network. Such a mechanism allows an ultrafast switching of the catalytic proton wire environment, possibly related to the exceptionally high KSI catalytic power.

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Section: Resultssupporting

confidence: 85%

Extreme Catalytic Power of Ketosteroid Isomerase Related to the Reversal of Proton Dislocations in Hydrogen-Bond Network

2020

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“…There are also reports about the effects of electric fields (both in the inorganic and biological milieu) on chemical reactions, as the field can significantly alter the potential energy curves near the transition state region governing chemical reactions [8] and consequently influence course and rate constants of the reactions [9][10][11][12]. Most effects can be comprehended as the field-induced stabilization of ionic structures [16].…”

Section: Introductionmentioning

confidence: 99%

The response of electronic and energetic properties of conjugated vs aromatic molecules to an external uniform electric field

Sadlej-Sosnowska

2019

Struct Chem

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The susceptibility of electric and energetic properties of two sets of molecules to perturbation in a uniform electric field was investigated. The molecules of one set were deca-1,3,5,7-pentaene terminated with two functional groups, R 1 and R 2 ; those of the second set were 4-R 1-4′-R 2-p-diphenylbenzenes, with R 1 and R 2 being the same as in the polyene set. The polyene and aromatic molecules had similar lengths of the system of conjugated bonds between the two most extreme carbon atoms. Dipole moments were used as determinants of the overall charge transfer within the molecules. The electric field was directed along the main (longest) axes of the molecules from the negative pole to the positive. Comparison of the effect of the charge relocation in both sets of conjugated molecules revealed that the charge transfer imposed by the electric field was more efficient in the polyenes than in the aromatic compounds; however, for the molecule pairs with the same R 1 and R 2 , reversal of the dipole moment direction falls at the same field strength. Parabolic dependence of the molecules' energy as a function of field strength can also be interpreted in terms of the response of electron density to an electric field.

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“…[8][9][10][11][12] One of the most studied enzymes in the context of understanding electrostatic preorganization is ketosteroid isomerase (KSI) ( Figure 1). Subjected to both theoretical and experimental interrogations, KSI has one of the highest known unimolecular rate constants 13,14 with many theoretical [15][16][17][18][19][20][21] and experimental [22][23][24][25][26] studies investigating its electrostatic preorganization. KSI catalyzes the isomerization of a steroid by altering the position of a C=C double bond through formation of a charged enolate after a proton abstraction and reinserting the proton two carbons away (Scheme 1).…”

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confidence: 99%

“…Optimized structures and reaction barriers for the active site of WT-KSI with and without a uniform external electric field were taken from our previous study. 16 Uniform electric fields of magnitude 10 MV/cm were applied one at a time to the system in the directions shown in Additionally, it has been shown that mutating tyrosines involved in the extended hydrogen bonding network surrounding the carbonyl oxygen (Y16, Y32, Y57) to 3−chlorotyrosines can reduce the ! "# to 1/5 of that of the wildtype rate.…”

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confidence: 99%

Direct Look at the Electric Field in Ketosteroid Isomerase and Its Variants

Hennefarth

Alexandrova

2020

ACS Catal.

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Enzymes catalyze a number of reactions with high efficiency and stereoselectivity. It is thought that strong, direct, and permanent electric fields within the active site of the enzyme contribute to the superb catalytic efficiency of enzymes. This effect is called electrostatic preorganization. Most often, electrostatic preorganization is analyzed by evaluating the local electric field at discrete points, such as a bond center, using, for example, vibrational Stark spectroscopy. However, the protein macromolecule creates a significantly more complicated heterogeneous electric field that affects the entire active site, whose total change density thus gets perturbed, with the implications for the catalytic mechanism. We present a global distribution of streamlines method to analyze the topology of the heterogeneous electric fields in within an enzyme active site. We focus on ketosteroid isomerase (KSI), an enzyme known to produce a field on the order of 100 MV/cm along the critical carbonyl bond in the steroid substrate. We investigate how mutations known to cause activity changes, as well as applied small external electric fields perturb the electric fields in the KSI active site. Where classical single-point analysis failed, using our method allowed us to properly correlate global changes in the electric field to changes in the reaction barrier. We were able to show that topologically similar local electric fields had similar reaction barriers.

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Charge Density in Enzyme Active Site as a Descriptor of Electrostatic Preorganization

Cited by 44 publications

References 52 publications

Extreme Catalytic Power of Ketosteroid Isomerase Related to the Reversal of Proton Dislocations in Hydrogen-Bond Network

Extreme Catalytic Power of Ketosteroid Isomerase Related to the Reversal of Proton Dislocations in Hydrogen-Bond Network

The response of electronic and energetic properties of conjugated vs aromatic molecules to an external uniform electric field

Direct Look at the Electric Field in Ketosteroid Isomerase and Its Variants

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