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Quantum Chemical Modeling of Phosphoesterase Mimics and Chemistry in Confined Spaces
Stockholm University, Faculty of Science, Department of Organic Chemistry.
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis, density functional theory is employed in the study of two kinds of systems that can be considered to be biomimetic in their own ways. First, three binuclear metal complexes, synthesized by the group of Prof. Ebbe Nordlander, have been investigated. The complexes are designed to resemble the active sites of phosphatase enzymes and have been examined in complexes where either two Zn(II) ions or one Fe(III) and one Mn(II) ion are bound. These dinuclear compounds were studied as catalysts for the hydrolysis of bis(2,4-dinitrophenyl) phosphate and the transesterification of 2-hydroxypropyl p-nitrophenyl phosphate, which are model systems for the same reactions occurring in DNA or RNA. It was found that the two reactions take place in similar ways: a hydroxide ion that is terminally bound to one of the metal centers acts either as a nucleophile in the hydrolysis reaction or as a base in the transesterification. The leaving groups depart in an effectively concerted manner, and the formed catalyst-product complexes are predicted to be the resting states of the catalytic cycles. The rate-determining free energy barriers are identified from the catalyst-product complex in one catalytic cycle to the transition state of nucleophilic attack in the next.

Another type of biomimetic modeling is made with an aim of imitating the conceptual features of selective binding of guests and screening them from solute-solvent interactions. Such features are found in so-called nanocontainers, and this thesis is concerned with studies of two capsules synthesized by the group of Prof. Julius Rebek, Jr. First, the cycloaddition of phenyl acetylene and phenyl azide has experimentally been observed to be accelerated in the presence of a capsule. Computational studies were herein performed on this system, and a previously unrecognized structure of the capsule is discovered. Two main factors are then identified as sources of the rate acceleration compared to the uncatalyzed reaction, namely the reduction of the entropic component and the selective destabilization of the reactant supercomplex over the transition state.

In the second capsule study, the alkane binding trends of a water-soluble cavitand was studied. It is found that implicit solvation models fail severely in reproducing the experimental equilibrium observed between binding of n-decane by the cavitand monomer and encapsulation in the capsule dimer. A mixed explicit/implicit solvation protocol is developed to better quantify the effect of hydrating the cavitand, and a simple correction to the hydration free energy of a single water molecule is proposed to remedy this. The resulting scheme is used to predict new hydration free energies of the cavitand complexes, resulting in significant improvement vis-à-vis experiments.

The computational results presented in this thesis show the usefulness of the quantum chemical calculations to develop understanding of experimental trends observed for substrate binding and catalysis. In particular, the methodology is shown to be versatile enough such that experimental observations can be reproduced for such diverse systems as studied herein.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University , 2017. , 59 p.
Keyword [en]
density functional theory, catalysis, phosphoester hydrolysis, transesterification, supramolecular chemistry, inclusion complex, host-guest chemistry, cycloaddition
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-148259ISBN: 978-91-7797-016-3 (print)ISBN: 978-91-7797-017-0 (electronic)OAI: oai:DiVA.org:su-148259DiVA: diva2:1150587
Public defence
2017-12-01, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 14:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 5: Manuscript.

Available from: 2017-11-08 Created: 2017-10-19 Last updated: 2017-11-08Bibliographically approved
List of papers
1. Theoretical Study of Phosphodiester Hydrolysis and Transesterification Catalyzed by an Unsymmetric Biomimetic Dizinc Complex
Open this publication in new window or tab >>Theoretical Study of Phosphodiester Hydrolysis and Transesterification Catalyzed by an Unsymmetric Biomimetic Dizinc Complex
2016 (English)In: Inorganic Chemistry, ISSN 0020-1669, E-ISSN 1520-510X, Vol. 55, no 4, 1872-1882 p.Article in journal (Refereed) Published
Abstract [en]

Density functional theory calculations have been used to investigate the reaction mechanisms of phosphodiester hydrolysis and transesterification catalyzed by a dinuclear zinc complex of the 2-(N-isopropyl-N-((2-pyridyl)methyl)-aminomethyl)-6-(N-(carboxylmethyl)-N-((2-pyridyl)methyl)amino-methyl)-4-methylphenol (IPCPMP) ligand, mimicking the active site of zinc phosphotriesterase. The substrates bis(2,4)-dinitrophenyl phosphate (BDNPP) and 2-hydroxypropyl-p-nitrophenyl phosphate (HPNP) were employed as analogues of DNA and RNA, respectively. A number of different mechanistic proposals were considered, with the active catalyst harboring either one or two hydroxide ions. It is concluded that for both reactions the catalyst has only one hydroxide bound, as this option yields lower overall energy barriers. For BDNPP hydrolysis, it is suggested that the hydroxide acts as the nucleophile in the reaction, attacking the phosphorus center of the substrate. For HPNP transesterification, on the other hand, the hydroxide is proposed to act as a Bronsted base, deprotonating the alcohol moiety of the substrate, which in turn performs the nucleophilic attack. The calculated overall barriers are in good agreement with measured rates. Both reactions are found to proceed by essentially concerted associative mechanisms, and it is demonstrated that two consecutive catalytic cycles need to be considered in order to determine the rate-determining free energy barrier.

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-128552 (URN)10.1021/acs.inorgchem.5b02733 (DOI)000370395000060 ()26812142 (PubMedID)
Available from: 2016-06-17 Created: 2016-03-30 Last updated: 2017-10-19Bibliographically approved
2. A dinuclear zinc(II) complex of a new unsymmetric ligand with an N(5)0(2) donor set; A structural and functional model for the active site of zinc phosphoesterases
Open this publication in new window or tab >>A dinuclear zinc(II) complex of a new unsymmetric ligand with an N(5)0(2) donor set; A structural and functional model for the active site of zinc phosphoesterases
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2014 (English)In: Journal of Inorganic Biochemistry, ISSN 0162-0134, E-ISSN 1873-3344, Vol. 132, 6-17 p.Article in journal (Refereed) Published
Abstract [en]

The dinuclear complex [Zn-2(DPCPMP)(pivalate)](C10(4)), where DPCPMP is the new unsymmetrical ligand [2-(N-(3-((bis((pyridin-2-yl)methyl)amino)methyl)-2-hydroxy-5-methylbenzyl)-N-((pyridin2-y1)methyl)amino)acetic acid], has been synthesized and characterized. The complex is a functional model for zinc phosphoesterases with dinuclear active sites. The hydrolytic efficacy of the complex has been investigated using bis-(2,4-dinitrophenyl)phosphate(BDNPP), a DNA analog, as substrate. Speciation studies using potentiometric titrations have been performed for both the ligand and the corresponding dizinc complex to elucidate the formation of the active hydrolysis catalyst; they reveals that the dinuclear zinc(II) complexes, [Zn-2(DPCPMP)](2) and [Zn-2(DPCPMP)(OH)1 predominate the solution above pH 4. The relatively high pKa of 8.38 for water deprotonation suggests that a terminal hydroxide complex is formed. Kinetic investigations of BDNPP hydrolysis over the pH range 5.5-11.0 and with varying metal to ligand ratio (metal salt:ligand = 0.5:1 to 3:1) have been performed. Variable temperature studies gave the activation parameters triangle H double dagger = 95.6 kJ mol(-1), triangle S double dagger = 44.8 J mo1(-1) K-1, and 6,triangle G double dagger = 108.0 kJ mo1-1. The cumulative results indicate the hydroxido-bridged dinuclear Zn(II) complex [Zn-2(DPCPMP)(mu-OH)] (+) as the effective catalyst. The mechanism of hydrolysis has been probed by computational modeling using density functional theory (DFF). Calculations show that the reaction goes through one concerted step (S(N)2 type) in which the bridging hydroxide in the transition state becomes terminal and performs a nucleophilic attack on the BDNPP phosphorus; the leaving group dissociates simultaneously in an overall inner sphere type activation. The calculated free energy barrier is in good agreement with the experimentally determined activation parameters.

Keyword
Zinc phosphoesterases, Dinuclear active sites, DNA analog, Transition state
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-102972 (URN)10.1016/j.jinorgbio.2013.08.001 (DOI)000333443800003 ()
Funder
Knut and Alice Wallenberg FoundationGöran Gustafsson Foundation for Research in Natural Sciences and MedicineSwedish Institute
Note

AuthorCount:10;

Available from: 2014-04-28 Created: 2014-04-25 Last updated: 2017-10-20Bibliographically approved
3. A Heterobimetallic FeIIIMnII Complex of an Unsymmetrical Dinucleating Ligand: A Structural and Functional Model Complex for the Active Site of Purple Acid Phosphatase of Sweet Potato
Open this publication in new window or tab >>A Heterobimetallic FeIIIMnII Complex of an Unsymmetrical Dinucleating Ligand: A Structural and Functional Model Complex for the Active Site of Purple Acid Phosphatase of Sweet Potato
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2014 (English)In: European Journal of Inorganic Chemistry, ISSN 1434-1948, E-ISSN 1099-1948, Vol. 2014, no 13, 2204-2212 p.Article in journal (Refereed) Published
Abstract [en]

The heterodinuclear mixed-valence complex [FeMn(ICIMP)(OAc)(2)Cl] (1) {H2ICIMP = 2-(N-carboxylmethyl)-[N-(N-methylimidazolyl-2-methyl)aminomethyl]-[6-(N-isopropylmethyl)-[N-(N-methylimidazolyl-2-methyl)]aminomethyl-4-methylphenol], an unsymmetrical N4O2 donor ligand} has been synthesized and fully characterized by several spectroscopic techniques as well as by X-ray crystallography. The crystal structure of the complex reveals that both metal centers in 1 are six-coordinate with the chloride ion occupying the sixth coordination site of the Mn-II ion. The phenoxide moiety of the ICIMP ligand and both acetate ligands bridge the two metal ions of the complex. Mossbauer spectroscopy shows that the iron ion in 1 is high-spin Fe-III. Two quasi-reversible redox reactions for the complex, attributed to the (FeMnII)-Mn-III/(FeMnII)-Mn-II (at -0.67 V versus Fc/Fc(+)) and (FeMnII)-Mn-III/(FeMnIII)-Mn-III (at 0.84 V), were observed by means of cyclic voltammetry. Complex 1, with an Fe-III-Mn-II distance of 3.58 angstrom, may serve as a model for the mixed-valence oxidation state of purple acid phosphatase from sweet potato. The capability of the complex to effect organophosphate hydrolysis (phosphatase activity) has been investigated at different pH levels (5.5-11) by using bis(2,4-dinitrophenyl)phosphate (BDNPP) as the substrate. Density functional theory calculations indicate that the substrate coordinates to the Mn-II ion. In the transition state, a hydroxide ion that bridges the two metal ions becomes terminally coordinated to the Fe-III ion and acts as a nucleophile, attacking the phosphorus center of BDNPP with the concomitant dissociation of the leaving group.

Keyword
Metalloenzymes, Mixed-valent compounds, Moessbauer spectroscopy, Density functional calculations, Transition states, Hydrolysis
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-105221 (URN)10.1002/ejic.201301375 (DOI)000335197600004 ()
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council
Note

AuthorCount:11;

Available from: 2014-07-03 Created: 2014-06-24 Last updated: 2017-10-19Bibliographically approved
4. Quantum Chemical Modeling of Cycloaddition Reaction in a Self-Assembled Capsule
Open this publication in new window or tab >>Quantum Chemical Modeling of Cycloaddition Reaction in a Self-Assembled Capsule
2017 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126Article in journal (Refereed) Epub ahead of print
Abstract [en]

Dispersion-corrected density functional theory is used to study the cycloaddition reaction between phenyl acetylene and phenyl azide inside a synthetic, self-assembled capsule. The capsule is first characterized computationally and a previously unrecognized structure is identified as being the most stable. Next, an examination of the free energies of host-guest complexes is conducted, considering all possible reagent, solvent and solvent impurity combinations as guests. The experimentally observed relative stabilities of host-guest complexes are quite well reproduced, when the experimental concentrations are taken into account. Experimentally, the presence of the host capsule has been shown to accelerate the cycloaddition reaction and to yield exclusively the 1,4-regioisomer product. Both these observations are reproduced by the calculations. A detailed energy decomposition analysis shows that reduction of the entropic cost of bringing together the reactants along with a geometric destabilization of the reactant supercomplex are the major contributors to the rate acceleration compared to the background reaction. Finally, a sensitivity analysis is conducted to assess the stability of the results with respect to the choice of methodology.

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-148255 (URN)10.1021/jacs.7b09102 (DOI)
Available from: 2017-10-19 Created: 2017-10-19 Last updated: 2017-10-20
5. Toward Accurate Quantum Chemical Modeling of Water-Soluble Self-Assembled Capsules
Open this publication in new window or tab >>Toward Accurate Quantum Chemical Modeling of Water-Soluble Self-Assembled Capsules
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-148258 (URN)
Available from: 2017-10-19 Created: 2017-10-19 Last updated: 2017-10-20Bibliographically approved

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1112131415161714 of 31
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