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Vern L Schramm - One of the best experts on this subject based on the ideXlab platform.
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the Transition State Structure for human mat2a from isotope effects
Journal of the American Chemical Society, 2017Co-Authors: Ross S Firestone, Vern L SchrammAbstract:Human methionine S-adenosyltransferase (MAT2A) catalyzes the formation of S-adenosylmethionine (SAM) from ATP and methionine. Synthetic lethal genetic analysis has identified MAT2A as an anti-cancer target in tumor cells lacking expression of 5-methylthioadenosine phosphorylase (MTAP). Approximately 15% of human cancers are MTAP-/-. The remainder can be rendered MTAP- through MTAP inhibitors. We used kinetic isotope effect (KIE), commitment factor (Cf), and binding isotope effect (BIE) measurements combined with quantum mechanical and molecular mechanic (QM/MM) calculations to solve the Transition State Structure of human MAT2A. The reaction is characterized by an advanced SN2 Transition State. Bond forming from the nucleophilic methionine sulfur to the 5'-C of ATP is 2.03 A at the Transition State (bond order of 0.67). Departure of the leaving group tripolyphosphate of ATP is well advanced and forms a 2.32 A bond between the 5'-C of ATP and the oxygen of the tripolyphosphate (bond order of 0.23). Intera...
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Kinetic Isotope Effects and Transition State Structure for Human Phenylethanolamine N-Methyltransferase
ACS Chemical Biology, 2016Co-Authors: Christopher F Stratton, Myles B. Poulin, Quan Du, Vern L SchrammAbstract:Phenylethanolamine N-methyltransferase (PNMT) catalyzes the S-adenosyl-l-methionine (SAM)-dependent conversion of norepinephrine to epinephrine. Epinephrine has been associated with critical processes in humans including the control of respiration and blood pressure. Additionally, PNMT activity has been suggested to play a role in hypertension and Alzheimer’s disease. In the current study, labeled SAM substrates were used to measure primary methyl-14C and 36S and secondary methyl-3H, 5′-3H, and 5′-14C intrinsic kinetic isotope effects for human PNMT. The Transition State of human PNMT was modeled by matching kinetic isotope effects predicted via quantum chemical calculations to intrinsic values. The model provides information on the geometry and electrostatics of the human PNMT Transition State Structure and indicates that human PNMT catalyzes the formation of epinephrine through an early SN2 Transition State in which methyl transfer is rate-limiting.
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Transition State Structure and Inhibition of Rv0091, a 5'-Deoxyadenosine/5'-methylthioadenosine Nucleosidase from Mycobacterium tuberculosis.
ACS Chemical Biology, 2016Co-Authors: Hilda A. Namanja-magliano, Christopher F Stratton, Vern L SchrammAbstract:5′-Methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) is a bacterial enzyme that catalyzes the hydrolysis of the N-ribosidic bond in 5′-methylthioadenosine (MTA) and S-adenosylhomocysteine (SAH). MTAN activity has been linked to quorum sensing pathways, polyamine biosynthesis, and adenine salvage. Previously, the coding sequence of Rv0091 was annotated as a putative MTAN in Mycobacterium tuberculosis. Rv0091 was expressed in Escherichia coli, purified to homogeneity, and shown to be a homodimer, consistent with MTANs from other microorganisms. Substrate specificity for Rv0091 gave a preference for 5′-deoxyadenosine relative to MTA or SAH. Intrinsic kinetic isotope effects (KIEs) for the hydrolysis of [1′-3H], [1′-14C], [5′-3H2], [9-15N], and [7-15N]MTA were determined to be 1.207, 1.038, 0.998, 1.021, and 0.998, respectively. A model for the Transition State Structure of Rv0091 was determined by matching KIE values predicted via quantum chemical calculations to the intrinsic KIEs. The transiti...
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human dnmt1 Transition State Structure
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Quan Du, Zhen Wang, Vern L SchrammAbstract:Human DNA methyltransferase 1 (DNMT1) maintains the epigenetic State of DNA by replicating CpG methylation signatures from parent to daughter strands, producing heritable methylation patterns through cell divisions. The proposed catalytic mechanism of DNMT1 involves nucleophilic attack of Cys 1226 to cytosine (Cyt) C6, methyl transfer from S -adenosyl-l-methionine (SAM) to Cyt C5, and proton abstraction from C5 to form methylated CpG in DNA. Here, we report the subangstrom geometric and electrostatic Structure of the major Transition State (TS) of the reaction catalyzed by human DNMT1. Experimental kinetic isotope effects were used to guide quantum mechanical calculations to solve the TS Structure. Methyl transfer occurs after Cys 1226 attack to Cyt C6, and the methyl transfer step is chemically rate-limiting for DNMT1. Electrostatic potential maps were compared for the TS and ground States, providing the electronic basis for interactions between the protein and reactants at the TS. Understanding the TS of DNMT1 demonstrates the possibility of using similar analysis to gain subangstrom geometric insight into the complex reactions of epigenetic modifications.
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Transition State Structure of rna depurination by saporin l3
ACS Chemical Biology, 2016Co-Authors: Hongling Yuan, Christopher F Stratton, Vern L SchrammAbstract:Saporin L3 from the leaves of the common soapwort is a catalyst for hydrolytic depurination of adenine from RNA. Saporin L3 is a type 1 ribosome inactivating protein (RIP) composed only of a catalytic domain. Other RIPs have been used in immunotoxin cancer therapy, but off-target effects have limited their development. In the current study, we use Transition State theory to understand the chemical mechanism and Transition State Structure of saporin L3. In favorable cases, Transition State Structures guide the design of Transition State analogues as inhibitors. Kinetic isotope effects (KIEs) were determined for an A14C mutant of saporin L3. To permit KIE measurements, small stem–loop RNAs that contain an AGGG tetraloop Structure were enzymatically synthesized with the single adenylate bearing specific isotopic substitutions. KIEs were measured and corrected for forward commitment to obtain intrinsic values. A model of the Transition State Structure for depurination of stem–loop RNA (5′-GGGAGGGCCC-3′) by sa...
Olle Matsson - One of the best experts on this subject based on the ideXlab platform.
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Determining the Transition-State Structure for Different SN2 Reactions Using Experimental Nucleophile Carbon and Secondary α-Deuterium Kinetic Isotope Effects and Theory
Journal of Physical Chemistry A, 2008Co-Authors: Kenneth Charles Westaway, Olle Matsson, Yao-ren Fang, Susanna Macmillar, Raymond A. Poirier, Shahidul M. IslamAbstract:Nucleophile 11C/14C [k11/k14] and secondary α-deuterium [(kH/kD)α] kinetic isotope effects (KIEs) were measured for the SN2 reactions between tetrabutylammonium cyanide and ethyl iodide, bromide, chloride, and tosylate in anhydrous DMSO at 20 °C to determine whether these isotope effects can be used to determine the Structure of SN2 Transition States. Interpreting the experimental KIEs in the usual fashion (i.e., that a smaller nucleophile KIE indicates the Nu−Cα Transition State bond is shorter and a smaller (kH/kD)α is found when the Nu−LG distance in the Transition State is shorter) suggests that the Transition State is tighter with a slightly shorter NC−Cα bond and a much shorter Cα−LG bond when the substrate has a poorer halogen leaving group. Theoretical calculations at the B3LYP/aug-cc-pVDZ level of theory support this conclusion. The results show that the experimental nucleophile 11C/14C KIEs can be used to determine Transition-State Structure in different reactions and that the usual method of in...
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Secondary deuterium kinetic isotope effects and Transition State Structure
Advances in Physical Organic Chemistry, 2008Co-Authors: Olle Matsson, Kenneth Charles WestawayAbstract:Publisher Summary This chapter is concerned with secondary deuterium kinetic isotope effects. The chapter illustrates some of the important recent advances in the interpretation and uses of these kinetic isotope effects to elucidate reaction mechanisms. Other excellent reviews of secondary deuterium kinetic isotope effects (KIEs) have also been discussed in the chapter. The chapter demonstrates the ways in which secondary deuterium and tritium KIEs can be used to elucidate the mechanisms of reactions and determine the Structure of their Transition States. Secondary a-deuterium KIEs have been widely used to determine the mechanism of S N reactions and to elucidate the Structure of their Transition States. Some of the significant studies illustrating these principles are presented in this chapter. In particular, the advantages of using both theoretical calculations and experimental data to solve these problems have been emphasized in the chapter.
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A theoretical investigation of α-carbon kinetic isotope effects and their relationship to the Transition-State Structure of SN2 reactions
Journal of Organic Chemistry, 2005Co-Authors: Olle Matsson, Agnieszka Dybala-defratyka, Michal Rostkowski, Piotr Paneth, Kenneth Charles WestawayAbstract:The Transition Structures and α-carbon 12C/13C kinetic isotope effects for 22 SN2 reactions between methyl chloride and a wide variety of nucleophiles have been calculated using the B1LYP/aug-cc-pVDZ level of theory. Anionic, neutral, and radical anion nucleophiles were used to give a wide range of SN2 Transition States so the relationship between the magnitude of the α-carbon kinetic isotope effect and Transition-State Structure could be determined. The results suggest that the α-carbon 12C/13C kinetic isotope effects for SN2 reactions will be large (near the experimental maximum) and that the curve relating the magnitude of the KIE to the percent transfer of the α-carbon from the nucleophile to the leaving group in the Transition State has a broad maximum. This means very similar KIEs will be found for early, symmetric, and late Transition States and that one cannot use the magnitude of these KIEs to estimate Transition-State Structure.
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Experimental and Theoretical Multiple Kinetic Isotope Effects for an SN2 Reaction. An Attempt to Determine Transition‐State Structure and the Ability of Theoretical Methods to Predict Experimental Kinetic Isotope Effects
Chemistry: A European Journal, 2003Co-Authors: Yao-ren Fang, Agnieszka Dybala-defratyka, Piotr Paneth, Per Ryberg, Jonas Eriksson, Magdalena Kołodziejska-huben, S. Madhavan, Rolf Danielsson, Olle MatssonAbstract:: The secondary alpha-deuterium, the secondary beta-deuterium, the chlorine leaving-group, the nucleophile secondary nitrogen, the nucleophile (12)C/(13)C carbon, and the (11)C/(14)C alpha-carbon kinetic isotope effects (KIEs) and activation parameters have been measured for the S(N)2 reaction between tetrabutylammonium cyanide and ethyl chloride in DMSO at 30 degrees C. Then, thirty-nine readily available different theoretical methods, both including and excluding solvent, were used to calculate the Structure of the Transition State, the activation energy, and the kinetic isotope effects for the reaction. A comparison of the experimental and theoretical results by using semiempirical, ab initio, and density functional theory methods has shown that the density functional methods are most successful in calculating the experimental isotope effects. With two exceptions, including solvent in the calculation does not improve the fit with the experimental KIEs. Finally, none of the Transition States and force constants obtained from the theoretical methods was able to predict all six of the KIEs found by experiment. Moreover, none of the calculated Transition Structures, which are all early and loose, agree with the late (product-like) Transition-State Structure suggested by interpreting the experimental KIEs.
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using 11c 14c incoming group and secondary α deuterium kies to determine how a change in leaving group alters the Structure of the Transition State of the sn2 reactions between m chlorobenzyl para substituted benzenesulfonates and cyanide ion
Journal of the American Chemical Society, 1998Co-Authors: Kenneth Charles Westaway, Yao-ren Fang, Jonas Persson, Olle MatssonAbstract:The 11C/14C incoming group and secondary α-deuterium KIEs and Hammett ρ value found by changing the substituent in the leaving group of the SN2 reactions between meta-chlorobenzyl para-substituted benzenesulfonates and cyanide ion in 0.5% aqueous acetonitrile at 0 °C suggest that these reactions occur via an unsymmetrical, product-like Transition State. Changing to a better leaving group leads to a Transition State with a slightly shorter nucleophile−α-carbon bond and a longer α-carbon−leaving group bond. The changes in Transition State Structure are consistent with the Bond Strength Hypothesis.
Kenneth Charles Westaway - One of the best experts on this subject based on the ideXlab platform.
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Determining the Transition-State Structure for Different SN2 Reactions Using Experimental Nucleophile Carbon and Secondary α-Deuterium Kinetic Isotope Effects and Theory
Journal of Physical Chemistry A, 2008Co-Authors: Kenneth Charles Westaway, Olle Matsson, Yao-ren Fang, Susanna Macmillar, Raymond A. Poirier, Shahidul M. IslamAbstract:Nucleophile 11C/14C [k11/k14] and secondary α-deuterium [(kH/kD)α] kinetic isotope effects (KIEs) were measured for the SN2 reactions between tetrabutylammonium cyanide and ethyl iodide, bromide, chloride, and tosylate in anhydrous DMSO at 20 °C to determine whether these isotope effects can be used to determine the Structure of SN2 Transition States. Interpreting the experimental KIEs in the usual fashion (i.e., that a smaller nucleophile KIE indicates the Nu−Cα Transition State bond is shorter and a smaller (kH/kD)α is found when the Nu−LG distance in the Transition State is shorter) suggests that the Transition State is tighter with a slightly shorter NC−Cα bond and a much shorter Cα−LG bond when the substrate has a poorer halogen leaving group. Theoretical calculations at the B3LYP/aug-cc-pVDZ level of theory support this conclusion. The results show that the experimental nucleophile 11C/14C KIEs can be used to determine Transition-State Structure in different reactions and that the usual method of in...
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Secondary deuterium kinetic isotope effects and Transition State Structure
Advances in Physical Organic Chemistry, 2008Co-Authors: Olle Matsson, Kenneth Charles WestawayAbstract:Publisher Summary This chapter is concerned with secondary deuterium kinetic isotope effects. The chapter illustrates some of the important recent advances in the interpretation and uses of these kinetic isotope effects to elucidate reaction mechanisms. Other excellent reviews of secondary deuterium kinetic isotope effects (KIEs) have also been discussed in the chapter. The chapter demonstrates the ways in which secondary deuterium and tritium KIEs can be used to elucidate the mechanisms of reactions and determine the Structure of their Transition States. Secondary a-deuterium KIEs have been widely used to determine the mechanism of S N reactions and to elucidate the Structure of their Transition States. Some of the significant studies illustrating these principles are presented in this chapter. In particular, the advantages of using both theoretical calculations and experimental data to solve these problems have been emphasized in the chapter.
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Determining Transition State Structure using kinetic isotope effects
Journal of Labelled Compounds and Radiopharmaceuticals, 2007Co-Authors: Kenneth Charles WestawayAbstract:Kinetic isotope effects (KIEs) have been found to be the most powerful tool available to physical organic chemists for determining the mechanism of reactions and for estimating the Structure of their Transition States. Various types of KIEs including primary-leaving group-, nucleophile-, and α-carbon KIEs and secondary alpha- and beta-deuterium KIEs are introduced. The factors that affect the magnitude of each of these KIEs are covered in some detail. Finally, the use of these KIEs to determine the mechanism of a reaction and to estimate the Structure of the Transition State for a reaction is discussed. Copyright © 2007 John Wiley & Sons, Ltd.
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A theoretical investigation of α-carbon kinetic isotope effects and their relationship to the Transition-State Structure of SN2 reactions
Journal of Organic Chemistry, 2005Co-Authors: Olle Matsson, Agnieszka Dybala-defratyka, Michal Rostkowski, Piotr Paneth, Kenneth Charles WestawayAbstract:The Transition Structures and α-carbon 12C/13C kinetic isotope effects for 22 SN2 reactions between methyl chloride and a wide variety of nucleophiles have been calculated using the B1LYP/aug-cc-pVDZ level of theory. Anionic, neutral, and radical anion nucleophiles were used to give a wide range of SN2 Transition States so the relationship between the magnitude of the α-carbon kinetic isotope effect and Transition-State Structure could be determined. The results suggest that the α-carbon 12C/13C kinetic isotope effects for SN2 reactions will be large (near the experimental maximum) and that the curve relating the magnitude of the KIE to the percent transfer of the α-carbon from the nucleophile to the leaving group in the Transition State has a broad maximum. This means very similar KIEs will be found for early, symmetric, and late Transition States and that one cannot use the magnitude of these KIEs to estimate Transition-State Structure.
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using 11c 14c incoming group and secondary α deuterium kies to determine how a change in leaving group alters the Structure of the Transition State of the sn2 reactions between m chlorobenzyl para substituted benzenesulfonates and cyanide ion
Journal of the American Chemical Society, 1998Co-Authors: Kenneth Charles Westaway, Yao-ren Fang, Jonas Persson, Olle MatssonAbstract:The 11C/14C incoming group and secondary α-deuterium KIEs and Hammett ρ value found by changing the substituent in the leaving group of the SN2 reactions between meta-chlorobenzyl para-substituted benzenesulfonates and cyanide ion in 0.5% aqueous acetonitrile at 0 °C suggest that these reactions occur via an unsymmetrical, product-like Transition State. Changing to a better leaving group leads to a Transition State with a slightly shorter nucleophile−α-carbon bond and a longer α-carbon−leaving group bond. The changes in Transition State Structure are consistent with the Bond Strength Hypothesis.
Andrew J. Bennet - One of the best experts on this subject based on the ideXlab platform.
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c2 oxyanion neighboring group participation Transition State Structure for the hydroxide promoted hydrolysis of 4 nitrophenyl α d mannopyranoside
Journal of the American Chemical Society, 2016Co-Authors: Gaetano Speciale, Marco Farrendai, Fahimeh S Shidmoossavee, Spencer J Williams, Andrew J. BennetAbstract:The hydroxide-catalyzed hydrolysis of aryl 1,2-trans-glycosides proceeds through a mechanism involving neighboring group participation by a C2-oxyanion and rate-limiting formation of a 1,2-anhydro sugar (oxirane) intermediate. The Transition State for the hydroxide-catalyzed hydrolysis of 4-nitrophenyl α-d-mannopyranoside in aqueous media has been studied by the use of multiple kinetic isotope effect (KIE) measurements in conjunction with ab initio theoretical methods. The experimental KIEs are C1-2H (1.112 ± 0.004), C2-2H (1.045 ± 0.005), anomeric 1-13C (1.026 ± 0.006), C2-13C (0.999 ± 0.005), leaving group oxygen 2-18O (1.040 ± 0.012), and C2-18O (1.044 ± 0.006). The Transition State for the hydrolysis reaction was modeled computationally using the experimental KIE values as constraints. Taken together, the reported kinetic isotope effects and computational modeling are consistent with the reaction mechanism involving rate-limiting formation of a transient oxirane intermediate that opens in water to giv...
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Transition State Structure for the hydronium ion promoted hydrolysis of α d glucopyranosyl fluoride
Canadian Journal of Chemistry, 2015Co-Authors: Jefferson Y Chan, Ariel Tang, Andrew J. BennetAbstract:The Transition State for the hydronium-ion-promoted hydrolysis of α-d-glucopyranosyl fluoride in water has been characterized by combining multiple kinetic isotope effect measurements with theoretical modelling. The measured kinetic isotope effects for the C1-deuterium, C2-deuterium, C5-deuterium, anomeric carbon-13, and ring oxygen-18 are 1.219 ± 0.021, 1.099 ± 0.024, 0.976 ± 0.014, 1.014 ± 0.005, and 0.991 ± 0.013, respectively. The Transition State for the hydronium ion reaction is late with respect to both C–F bond cleavage and proton transfer.
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Transition State Structure for the quintessential sn2 reaction of a carbohydrate reaction of α glucopyranosyl fluoride with azide ion in water
Journal of the American Chemical Society, 2014Co-Authors: Jefferson Y Chan, Ariel Tang, Natalia Sannikova, Andrew J. BennetAbstract:We report that the SN2 reaction of α-d-glucopyranosyl fluoride with azide ion proceeds through a loose (exploded) Transition-State (TS) Structure. We reached this conclusion by modeling the TS using a suite of five experimental kinetic isotope effects (KIEs) as constraints for the calculations. We also report that the anomeric 13C-KIE is not abnormally large (k12/k13 = 1.024 ± 0.006), a finding which is at variance with the previous literature value (Zhang et al. J. Am. Chem. Soc. 1994, 116, 7557).
Enyew A. Bayle - One of the best experts on this subject based on the ideXlab platform.
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Modeling the Transition State Structure to probe a reaction mechanism on the oxidation of quinoline by quinoline 2-oxidoreductase
Chemistry Central Journal, 2016Co-Authors: Enyew A. BayleAbstract:Background Quinoline 2-oxidoreductase (Qor) is a member of molybdenum hydroxylase which catalyzes the oxidation of quinoline (2, 3 benzopyridine) to 1-hydro-2-oxoquinoline. Qor has biological and medicinal significances. Qor is known to metabolize drugs produced from quinoline for the treatment of malaria, arthritis, and lupus for many years. However, the mechanistic action by which Qor oxidizes quinoline has not been investigated either experimentally or theoretically. Purpose of the study The present study was intended to determine the interaction site of quinoline, predict the Transition State Structure, and probe a plausible mechanistic route for the oxidative hydroxylation of quinoline in the reductive half-reaction active site of Qor. Results Density functional theory calculations have been carried out in order to understand the events taking place during the oxidative hydroxylation of quinoline in the reductive half-reaction active site of Qor. The most electropositivity and the lowest percentage contribution to the HOMO are shown at C_2 of quinoline compared to the other carbon atoms. The Transition State Structure of quinoline bound to the active site has been confirmed by one imaginary negative frequency of −104.500/s and −1.2365899E+06 Transition State energies. The Muliken atomic charges, the bond distances, and the bond order profiles were determined to characterize the Transition State Structure and the reaction mechanism. Conclusion The results have shown that C_2 is the preferred locus of interaction of quinoline to interact with the active site of Qor. The Transition State Structure of quinoline bound to the active site has been confirmed by one imaginary negative frequency. Moreover, the presence of partial negative charges on hydrogen at the Transitions State suggested hydride transfer. Similarly, results obtained from total energy, iconicity and molecular orbital analyses supported a concerted reaction mechanism.
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Modeling the Transition State Structure to probe a reaction mechanism on the oxidation of quinoline by quinoline 2-oxidoreductase.
Chemistry Central Journal, 2016Co-Authors: Enyew A. BayleAbstract:Quinoline 2-oxidoreductase (Qor) is a member of molybdenum hydroxylase which catalyzes the oxidation of quinoline (2, 3 benzopyridine) to 1-hydro-2-oxoquinoline. Qor has biological and medicinal significances. Qor is known to metabolize drugs produced from quinoline for the treatment of malaria, arthritis, and lupus for many years. However, the mechanistic action by which Qor oxidizes quinoline has not been investigated either experimentally or theoretically. The present study was intended to determine the interaction site of quinoline, predict the Transition State Structure, and probe a plausible mechanistic route for the oxidative hydroxylation of quinoline in the reductive half-reaction active site of Qor. Density functional theory calculations have been carried out in order to understand the events taking place during the oxidative hydroxylation of quinoline in the reductive half-reaction active site of Qor. The most electropositivity and the lowest percentage contribution to the HOMO are shown at C2 of quinoline compared to the other carbon atoms. The Transition State Structure of quinoline bound to the active site has been confirmed by one imaginary negative frequency of −104.500/s and −1.2365899E+06 Transition State energies. The Muliken atomic charges, the bond distances, and the bond order profiles were determined to characterize the Transition State Structure and the reaction mechanism. The results have shown that C2 is the preferred locus of interaction of quinoline to interact with the active site of Qor. The Transition State Structure of quinoline bound to the active site has been confirmed by one imaginary negative frequency. Moreover, the presence of partial negative charges on hydrogen at the Transitions State suggested hydride transfer. Similarly, results obtained from total energy, iconicity and molecular orbital analyses supported a concerted reaction mechanism.
