Change search
Link to record
Permanent link

Direct link
Publications (10 of 130) Show all publications
Sheng, X., Kroutil, W. & Himo, F. (2024). Computational Study of the Fries Rearrangement Catalyzed by Acyltransferase from Pseudomonas protegens. ChemistryOpen
Open this publication in new window or tab >>Computational Study of the Fries Rearrangement Catalyzed by Acyltransferase from Pseudomonas protegens
2024 (English)In: ChemistryOpen, ISSN 2191-1363Article in journal (Refereed) Epub ahead of print
Abstract [en]

The acyltransferase from Pseudomonas protegens (PpATase) catalyzes in nature the reversible transformation of monoacetylphloroglucinol to diacetylphloroglucinol and phloroglucinol. Interestingly, this enzyme has been shown to catalyze the promiscuous transformation of 3-hydroxyphenyl acetate to 2′,4′-dihydroxyacetophenone, representing a biological version of the Fries rearrangement. In the present study, we report a mechanistic investigation of this activity of PpATase using quantum chemical calculations. A detailed mechanism is proposed, and the energy profile for the reaction is presented. The calculations show that the acylation of the enzyme is highly exothermic, while the acetyl transfer back to the substrate is only slightly exothermic. The deprotonation of the C6−H of the substrate is rate-limiting, and a remote aspartate residue (Asp137) is proposed to be the general base group in this step. Analysis of the binding energies of various acetyl acceptors shows that PpATase can promote both intramolecular and intermolecular Fries rearrangement towards diverse compounds. 

Keywords
acyltransferase, biocatalysis, Fries rearrangement, reaction mechanism, cluster approach
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-226124 (URN)10.1002/open.202300256 (DOI)001143283100001 ()38224208 (PubMedID)2-s2.0-85182470763 (Scopus ID)
Available from: 2024-02-06 Created: 2024-02-06 Last updated: 2024-02-06
Biosca, M., Szabó, K. J. & Himo, F. (2024). Mechanism of Asymmetric Homologation of Alkenylboronic Acids with CF3-Diazomethane via Borotropic Rearrangement. Journal of Organic Chemistry, 89(7), 4538-4548
Open this publication in new window or tab >>Mechanism of Asymmetric Homologation of Alkenylboronic Acids with CF3-Diazomethane via Borotropic Rearrangement
2024 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 89, no 7, p. 4538-4548Article in journal (Refereed) Published
Abstract [en]

Density functional theory calculations have been performed to investigate the mechanism for the BINOL-catalyzed asymmetric homologation of alkenylboronic acids with CF3-diazomethane. The reaction proceeds via a chiral BINOL ester of the alkenylboronic acid substrate. The calculations reveal a complex scenario for the formation of the chiral BINOL-alkenylboronate species, which is the key intermediate in the catalytic process. The aliphatic alcohol additive plays an important role in the reaction. This study provides a rationalization of the stereoinduction step of the reaction, and the enantioselectivity is mainly attributed to the steric repulsion between the CF3 group of the diazomethane reagent and the γ-substituent of the BINOL catalyst. The complex potential energy surface obtained by the calculations is analyzed by means of microkinetic simulations.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-228130 (URN)10.1021/acs.joc.3c02785 (DOI)001191206600001 ()38527364 (PubMedID)2-s2.0-85188737949 (Scopus ID)
Available from: 2024-04-10 Created: 2024-04-10 Last updated: 2024-04-29Bibliographically approved
Norjmaa, G., Rebek Jr., J. & Himo, F. (2024). Modeling Amine Methylation in Methyl Ester Cavitand. Chemistry - A European Journal, 30(13), Article ID e202303911.
Open this publication in new window or tab >>Modeling Amine Methylation in Methyl Ester Cavitand
2024 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 30, no 13, article id e202303911Article in journal (Refereed) Published
Abstract [en]

Methylation of amines inside an introverted resorcinarene-based deep methyl ester cavitand is investigated by means of molecular dynamics simulations and quantum chemical calculations. Experimentally, the cavitand has been shown to bind a number of amines and accelerate the methylation reaction by more than four orders of magnitude for some of them. Eight different amines are considered in the present study, and the geometries and energies of their binding to the cavitand are first characterized and analyzed. Next, the methyl transfer reactions are investigated and the calculated barriers are found to be in generally good agreement with experimental results. In particular, the experimentally-observed rate acceleration in the cavitand as compared to the solution reaction is well reproduced by the calculations. The origins of this rate acceleration are analyzed by computational modifications made to the structure of the cavitand, and the role of the solvent is discussed.

Keywords
Density functional theory, cavitand, methylation, reaction mechanism, supramolecular chemistry
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:su:diva-226105 (URN)10.1002/chem.202303911 (DOI)001142280000001 ()38224206 (PubMedID)2-s2.0-85182496311 (Scopus ID)
Available from: 2024-02-07 Created: 2024-02-07 Last updated: 2024-04-29Bibliographically approved
Manna, S., Peters, J., Bermejo-López, A., Himo, F. & Bäckvall, J.-E. (2023). Mechanistic Studies on Iron-Catalyzed Dehydrogenation of Amines Involving Cyclopentadienone Iron Complexes-Evidence for Stepwise Hydride and Proton Transfer. ACS Catalysis, 13(13), 8477-8484
Open this publication in new window or tab >>Mechanistic Studies on Iron-Catalyzed Dehydrogenation of Amines Involving Cyclopentadienone Iron Complexes-Evidence for Stepwise Hydride and Proton Transfer
Show others...
2023 (English)In: ACS Catalysis, E-ISSN 2155-5435, Vol. 13, no 13, p. 8477-8484Article in journal (Refereed) Published
Abstract [en]

The mechanism of dehydrogenation of amines catalyzedby (cyclopentadienone)ironcarbonyl complexes was studied by means of kinetic isotope effect(KIE) measurements, intermediate isolation, and density functionaltheory calculations. The (cyclopentadienone)iron-amine intermediateswere isolated and characterized by H-1 and C-13 NMR spectroscopy as well as X-ray crystallography. The isolatediron-amine complexes are quite stable and undergo a formal beta-hydride elimination to produce imine and iron hydride complexes.The KIEs observed for the iron-catalyzed dehydrogenation of 4-methoxy-N-(4-methylbenzyl)aniline are in accordance with stepwisedehydrogenation. The density functional calculations corroborate astepwise mechanism involving a rate-determining hydride transfer fromamine to iron to yield a metal hydride and an iminium intermediate,followed by a proton transfer from the iminium ion to the oxygen ofthe cyclopentadienone ligand.

Keywords
iron catalysis, dehydrogenation, amines, hydrogen transfer, kinetic isotope effects, DFT calculations
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-229560 (URN)10.1021/acscatal.3c01779 (DOI)001004328500001 ()
Available from: 2024-05-24 Created: 2024-05-24 Last updated: 2024-05-24Bibliographically approved
Sheng, X. & Himo, F. (2023). The Quantum Chemical Cluster Approach in Biocatalysis. Accounts of Chemical Research, 56(8), 938-947
Open this publication in new window or tab >>The Quantum Chemical Cluster Approach in Biocatalysis
2023 (English)In: Accounts of Chemical Research, ISSN 0001-4842, E-ISSN 1520-4898, Vol. 56, no 8, p. 938-947Article, review/survey (Refereed) Published
Abstract [en]

CONSPECTUS: The quantum chemical cluster approach has been used for modeling enzyme active sites and reaction mechanisms for more than two decades. In this methodology, a relatively small part of the enzyme around the active site is selected as a model, and quantum chemical methods, typically density functional theory, are used to calculate energies and other properties. The surrounding enzyme is modeled using implicit solvation and atom fixing techniques. Over the years, a large number of enzyme mechanisms have been solved using this method. The models have gradually become larger as a result of the faster computers, and new kinds of questions have been addressed. In this Account, we review how the cluster approach can be utilized in the field of biocatalysis. Examples from our recent work are chosen to illustrate various aspects of the methodology. The use of the cluster model to explore substrate binding is discussed first. It is emphasized that a comprehensive search is necessary in order to identify the lowest-energy binding mode(s). It is also argued that the best binding mode might not be the productive one, and the full reactions for a number of enzyme–substrate complexes have therefore to be considered to find the lowest-energy reaction pathway. Next, examples are given of how the cluster approach can help in the elucidation of detailed reaction mechanisms of biocatalytically interesting enzymes, and how this knowledge can be exploited to develop enzymes with new functions or to understand the reasons for lack of activity toward non-natural substrates. The enzymes discussed in this context are phenolic acid decarboxylase and metal-dependent decarboxylases from the amidohydrolase superfamily. Next, the application of the cluster approach in the investigation of enzymatic enantioselectivity is discussed. The reaction of strictosidine synthase is selected as a case study, where the cluster calculations could reproduce and rationalize the selectivities of both the natural and non-natural substrates. Finally, we discuss how the cluster approach can be used to guide the rational design of enzyme variants with improved activity and selectivity. Acyl transferase from Mycobacterium smegmatis serves as an instructive example here, for which the calculations could pinpoint the factors controlling the reaction specificity and enantioselectivity. The cases discussed in this Account highlight thus the value of the cluster approach as a tool in biocatalysis. It complements experiments and other computational techniques in this field and provides insights that can be used to understand existing enzymes and to develop new variants with tailored properties.

National Category
Biocatalysis and Enzyme Technology Theoretical Chemistry
Identifiers
urn:nbn:se:su:diva-216904 (URN)10.1021/acs.accounts.2c00795 (DOI)000962315200001 ()36976880 (PubMedID)2-s2.0-85151367020 (Scopus ID)
Available from: 2023-05-15 Created: 2023-05-15 Last updated: 2023-10-04Bibliographically approved
Rahman, F.-U., Wang, R., Zhang, H.-B., Brea, O., Himo, F., Rebek, Jr., J. & Yu, Y. (2022). Binding and Assembly of a Benzotriazole Cavitand in Water. Angewandte Chemie International Edition, 61(29), Article ID e202205534.
Open this publication in new window or tab >>Binding and Assembly of a Benzotriazole Cavitand in Water
Show others...
2022 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 61, no 29, article id e202205534Article in journal (Refereed) Published
Abstract [en]

A water-soluble cavitand bearing a benzotriazole upper rim was prepared and characterized. It exists as a dimeric velcraplex in D2O, but forms host–guest complexes with hydrophobic and amphiphilic guests. Alkanes (C5 to C10), cyclic ketones (C6–C10), cyclic alcohols (C6–C8) and various amphiphilic guests form 1 : 1 cavitand complexes. A cyclic array of hydrogen bonds, bridged by solvent/water (D2O) molecules, stabilizes the vase conformation of the complexes. With longer alkanes (C12–C15), symmetrical dialkyl amine, urea and phosphate, 2 : 1 host:guest capsules are formed. Computations indicate that additional waters on the upper rim create a self-complementary hydrogen-bonding pattern for capsule formation. 

Keywords
Capsule in Water, Cavitands, Molecular Recognition, Water-Mediated Hydrogen Bonding
National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-206317 (URN)10.1002/anie.202205534 (DOI)000800568000001 ()35488890 (PubMedID)2-s2.0-85130625126 (Scopus ID)
Available from: 2022-06-22 Created: 2022-06-22 Last updated: 2022-09-24Bibliographically approved
Norjmaa, G., Himo, F., Maréchal, J.-D. & Ujaque, G. (2022). Catalysis by [Ga4L6]12− Metallocage on the Nazarov Cyclization: The Basicity of Complexed Alcohol is Key. Chemistry - A European Journal, 28(60), Article ID e202201792.
Open this publication in new window or tab >>Catalysis by [Ga4L6]12− Metallocage on the Nazarov Cyclization: The Basicity of Complexed Alcohol is Key
2022 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 28, no 60, article id e202201792Article in journal (Refereed) Published
Abstract [en]

The Nazarov cyclization is investigated in solution and within K12[Ga4L6] supramolecular organometallic cage by means of computational methods. The reaction needs acidic condition in solution but works at neutral pH in the presence of the metallocage. The reaction steps for the process are analogous in both media: (a) protonation of the alcohol group, (b) water loss and (c) cyclization. The relative Gibbs energies of all the steps are affected by changing the environment from solvent to the metallocage. The first step in the mechanism, the alcohol protonation, turns out to be the most critical one for the acceleration of the reaction inside the metallocage. In order to calculate the relative stability of protonated alcohol inside the cavity, we propose a computational scheme for the calculation of basicity for species inside cavities and can be of general use. These results are in excellent agreement with the experiments, identifying key steps of catalysis and providing an in-depth understanding of the impact of the metallocage on all the reaction steps.

Keywords
density functional theory, metallocage, molecular dynamics, Nazarov cyclization, supramolecular catalysis
National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-209772 (URN)10.1002/chem.202201792 (DOI)000848212500001 ()35859038 (PubMedID)2-s2.0-85137250712 (Scopus ID)
Available from: 2022-10-10 Created: 2022-10-10 Last updated: 2022-10-31Bibliographically approved
Prejanò, M., Sheng, X. & Himo, F. (2022). Computational Study of Mechanism and Enantioselectivity of Imine Reductase from Amycolatopsis orientalis. ChemistryOpen, 11(1), Article ID e202100250.
Open this publication in new window or tab >>Computational Study of Mechanism and Enantioselectivity of Imine Reductase from Amycolatopsis orientalis
2022 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 11, no 1, article id e202100250Article in journal (Refereed) Published
Abstract [en]

Imine reductases (IREDs) are NADPH-dependent enzymes (NADPH=nicotinamide adenine dinucleotide phosphate) that catalyze the reduction of imines to amines. They exhibit high enantioselectivity for a broad range of substrates, making them of interest for biocatalytic applications. In this work, we have employed density functional theory (DFT) calculations to elucidate the reaction mechanism and the origins of enantioselectivity of IRED from Amycolatopsis orientalis. Two substrates are considered, namely 1-methyl-3,4-dihydroisoquinoline and 2-propyl-piperideine. A model of the active site is built on the basis of the available crystal structure. For both substrates, different binding modes are first evaluated, followed by calculation of the hydride transfer transition states from each complex. We have also investigated the effect of mutations of certain important active site residues (Tyr179Ala and Asn241Ala) on the enantioselectivity. The calculated energies are consistent with the experimental observations and the analysis of transition states geometries provides insights into the origins of enantioselectivity of this enzyme. 

Keywords
biocatalysis, enantioselectivity, imine reductase, reaction mechanism, transition state
National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-199798 (URN)10.1002/open.202100250 (DOI)000722455400001 ()34825518 (PubMedID)
Available from: 2021-12-18 Created: 2021-12-18 Last updated: 2022-01-25Bibliographically approved
Matsuzawa, A., Harvey, J. N. & Himo, F. (2022). On the Importance of Considering Multinuclear Metal Sites in Homogeneous Catalysis Modeling. Topics in catalysis, 65(1-4), 96-104
Open this publication in new window or tab >>On the Importance of Considering Multinuclear Metal Sites in Homogeneous Catalysis Modeling
2022 (English)In: Topics in catalysis, ISSN 1022-5528, E-ISSN 1572-9028, Vol. 65, no 1-4, p. 96-104Article in journal (Refereed) Published
Abstract [en]

In this short review, we provide an account of a number of computational studies of catalytic reaction mechanisms carried out in our groups. We focus in particular on studies in which we came to realize during the course of the investigation that the active catalytic species was a bimetallic complex, rather a monometallic one as previously assumed. In some cases, this realization was in part prompted by experimental observations, but careful exploration based on computation of the speciation of the metal precursor also provided a powerful guide: it is often possible to predict that bimetallic species (intermediates or transition states) lie lower in free energy than a priori competitive monometallic species. In this sense, we argue that in organometallic catalysis, the rule whereby two is better than one turns out to be relevant much more often than one might expect.

Keywords
Homogenous catalysis, Quantum chemistry, Density functional theory, Modeling, Binuclear catalyst
National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-197879 (URN)10.1007/s11244-021-01507-z (DOI)000751454600008 ()
Available from: 2021-10-19 Created: 2021-10-19 Last updated: 2022-02-25Bibliographically approved
Prejanò, M., Škerlová, J., Stenmark, P. & Himo, F. (2022). Reaction Mechanism of Human PAICS Elucidated by Quantum Chemical Calculations. Journal of the American Chemical Society, 144(31), 14258-14268
Open this publication in new window or tab >>Reaction Mechanism of Human PAICS Elucidated by Quantum Chemical Calculations
2022 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 144, no 31, p. 14258-14268Article in journal (Refereed) Published
Abstract [en]

Human PAICS is a bifunctional enzyme that is involved in the de novo purine biosynthesis, catalyzing the conversion of aminoimidazole ribonucleotide (AIR) into N-succinylcarboxamide-5-aminoimidazole ribonucleo-tide (SAICAR). It comprises two distinct active sites, AIR carboxylase (AIRc) where the AIR is initially converted to carboxyaminoimidazole ribonucleotide (CAIR) by reaction with CO2 and SAICAR synthetase (SAICARs) in which CAIR then reacts with an aspartate to form SAICAR, in an ATP-dependent reaction. Human PAICS is a promising target for the treatment of various types of cancer, and it is therefore of high interest to develop a detailed understanding of its reaction mechanism. In the present work, density functional theory calculations are employed to investigate the PAICS reaction mechanism. Starting from the available crystal structures, two large models of the AIRc and SAICARs active sites are built and different mechanistic proposals for the carboxylation and phosphorylation-condensation mechanisms are examined. For the carboxylation reaction, it is demonstrated that it takes place in a two-step mechanism, involving a C-C bond formation followed by a deprotonation of the formed tetrahedral intermediate (known as isoCAIR) assisted by an active site histidine residue. For the phosphorylation-condensation reaction, it is shown that the phosphorylation of CAIR takes place before the condensation reaction with the aspartate. It is further demonstrated that the three active site magnesium ions are involved in binding the substrates and stabilizing the transition states and intermediates of the reaction. The calculated barriers are in good agreement with available experimental data.

Keywords
Atmospheric chemistry, Chemical calculations, Crystal structure, Monomers, Peptides and proteins
National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-208509 (URN)10.1021/jacs.2c05072 (DOI)000836017000001 ()35914774 (PubMedID)2-s2.0-85135768121 (Scopus ID)
Available from: 2022-08-30 Created: 2022-08-30 Last updated: 2022-08-30Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-1012-5611

Search in DiVA

Show all publications