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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Physical Chemistry, Theoretical and Computational Chemistry".

Deadline for manuscript submissions: closed (30 November 2016) | Viewed by 43365

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Dr. Samuel De Visser

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Manchester Institute of Biotechnology and School of Chemical Engineering and Analytical Science, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK
Interests: computational chemistry; density functional theory; QM/MM; reaction mechanisms; biomimetic models; enzyme catalysis
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Special Issue Information

Dear Colleagues,

Computational tools have advanced dramatically in recent years and now large (bio)chemical systems can be studied accurately with density functional theory as well as quantum mechanics/molecular mechanics methods. A popular use of the techniques is of a predictive nature in biotechnology and biocatalysis, where catalytic cycles and reaction schemes of enzymes are established that predict the formation of products and by-products and determine the rate determining steps in a reaction mechanism. This Special Issue in the International Journal of Molecular Science will be dedicated to the modelling of reaction mechanisms and reaction profiles relevant to biochemistry and aimed to elucidate biochemical reaction processes in enzymes and biocatalysts using computational tools.

Prof. Dr. Sam de Visser
Guest Editor

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Keywords

catalysis
(in)organic reaction mechanisms
predictions
regioselectivity
density functional theory

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Published Papers (7 papers)

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Research

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951 KiB

Open AccessArticle

The Peculiar Glycolytic Pathway in Hyperthermophylic Archaea: Understanding Its Whims by Experimentation In Silico

by Yanfei Zhang, Theresa Kouril, Jacky L. Snoep, Bettina Siebers, Matteo Barberis and Hans V. Westerhoff

Int. J. Mol. Sci. 2017, 18(4), 876; https://doi.org/10.3390/ijms18040876 - 20 Apr 2017

Cited by 9 | Viewed by 5136

Abstract

Mathematical models are key to systems biology where they typically describe the topology and dynamics of biological networks, listing biochemical entities and their relationships with one another. Some (hyper)thermophilic Archaea contain an enzyme, called non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase (GAPN), which catalyzes the direct oxidation of glyceraldehyde-3-phosphate to 3-phosphoglycerate omitting adenosine 5′-triphosphate (ATP) formation by substrate-level-phosphorylation via phosphoglycerate kinase. In this study we formulate three hypotheses that could explain functionally why GAPN exists in these Archaea, and then construct and use mathematical models to test these three hypotheses. We used kinetic parameters of enzymes of Sulfolobus solfataricus (S. solfataricus) which is a thermo-acidophilic archaeon that grows optimally between 60 and 90 °C and between pH 2 and 4. For comparison, we used a model of Saccharomyces cerevisiae (S. cerevisiae), an organism that can live at moderate temperatures. We find that both the first hypothesis, i.e., that the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) plus phosphoglycerate kinase (PGK) route (the alternative to GAPN) is thermodynamically too much uphill and the third hypothesis, i.e., that GAPDH plus PGK are required to carry the flux in the gluconeogenic direction, are correct. The second hypothesis, i.e., that the GAPDH plus PGK route delivers less than the 1 ATP per pyruvate that is delivered by the GAPN route, is only correct when GAPDH reaction has a high rate and 1,3-bis-phosphoglycerate (BPG) spontaneously degrades to 3PG at a high rate. Full article

(This article belongs to the Special Issue Computational Modelling of Enzymatic Reaction Mechanisms)

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5695 KiB

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Influence of Temperature on Transdermal Penetration Enhancing Mechanism of Borneol: A Multi-Scale Study

by Qianqian Yin, Ran Wang, Shufang Yang, Zhimin Wu, Shujuan Guo, Xingxing Dai, Yanjiang Qiao and Xinyuan Shi

Int. J. Mol. Sci. 2017, 18(1), 195; https://doi.org/10.3390/ijms18010195 - 19 Jan 2017

Cited by 12 | Viewed by 5199

Abstract

The influence of temperature on the transdermal permeation enhancing mechanism of borneol (BO) was investigated using a multi-scale method, containing a coarse-grained molecular dynamic (CG-MD) simulation, an in vitro permeation experiment, and a transmission electron microscope (TEM) study. The results showed that BO has the potential to be used as a transdermal penetration enhancer to help osthole (OST) penetrate into the bilayer. With the increasing temperature, the stratum corneum (SC) becomes more flexible, proving to be synergistic with the permeation enhancement of BO, and the lag time (T_Lag) of BO and OST are shortened. However, when the temperature increased too much, with the effect of BO, the structure of SC was destroyed; for example, a water pore was formed and the micelle reversed. Though there were a number of drugs coming into the SC, the normal bilayer structure was absent. In addition, through comparing the simulation, in vitro experiment, and TEM study, we concluded that the computer simulation provided some visually detailed information, and the method plays an important role in related studies of permeation. Full article

(This article belongs to the Special Issue Computational Modelling of Enzymatic Reaction Mechanisms)

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2419 KiB

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Distal [FeS]-Cluster Coordination in [NiFe]-Hydrogenase Facilitates Intermolecular Electron Transfer

by Alexander Petrenko and Matthias Stein

Int. J. Mol. Sci. 2017, 18(1), 100; https://doi.org/10.3390/ijms18010100 - 5 Jan 2017

Cited by 11 | Viewed by 5558

Abstract

Biohydrogen is a versatile energy carrier for the generation of electric energy from renewable sources. Hydrogenases can be used in enzymatic fuel cells to oxidize dihydrogen. The rate of electron transfer (ET) at the anodic side between the [NiFe]-hydrogenase enzyme distal iron–sulfur cluster and the electrode surface can be described by the Marcus equation. All parameters for the Marcus equation are accessible from Density Functional Theory (DFT) calculations. The distal cubane FeS-cluster has a three-cysteine and one-histidine coordination [Fe₄S₄](His)(Cys)₃ first ligation sphere. The reorganization energy (inner- and outer-sphere) is almost unchanged upon a histidine-to-cysteine substitution. Differences in rates of electron transfer between the wild-type enzyme and an all-cysteine mutant can be rationalized by a diminished electronic coupling between the donor and acceptor molecules in the [Fe₄S₄](Cys)₄ case. The fast and efficient electron transfer from the distal iron–sulfur cluster is realized by a fine-tuned protein environment, which facilitates the flow of electrons. This study enables the design and control of electron transfer rates and pathways by protein engineering. Full article

(This article belongs to the Special Issue Computational Modelling of Enzymatic Reaction Mechanisms)

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5374 KiB

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ns-μs Time-Resolved Step-Scan FTIR of ba₃ Oxidoreductase from Thermus thermophilus: Protonic Connectivity of w941-w946-w927

by Antonis Nicolaides, Tewfik Soulimane and Constantinos Varotsis

Int. J. Mol. Sci. 2016, 17(10), 1657; https://doi.org/10.3390/ijms17101657 - 29 Sep 2016

Cited by 7 | Viewed by 5587

Abstract

Time-resolved step-scan FTIR spectroscopy has been employed to probe the dynamics of the ba₃ oxidoreductase from Thermus thermophilus in the ns-μs time range and in the pH/pD 6–9 range. The data revealed a pH/pD sensitivity of the D372 residue and of the ring-A propionate of heme a₃. Based on the observed transient changes a model in which the protonic connectivity of w941-w946-927 to the D372 and the ring-A propionate of heme a₃ is described. Full article

(This article belongs to the Special Issue Computational Modelling of Enzymatic Reaction Mechanisms)

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3119 KiB

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How the Proximal Pocket May Influence the Enantiospecificities of Chloroperoxidase-Catalyzed Epoxidations of Olefins

by Alexander N. Morozov and David C. Chatfield

Int. J. Mol. Sci. 2016, 17(8), 1297; https://doi.org/10.3390/ijms17081297 - 9 Aug 2016

Cited by 7 | Viewed by 4362

Abstract

Chloroperoxidase-catalyzed enantiospecific epoxidations of olefins are of significant biotechnological interest. Typical enantiomeric excesses are in the range of 66%–97% and translate into free energy differences on the order of 1 kcal/mol. These differences are generally attributed to the effect of the distal pocket. In this paper, we show that the influence of the proximal pocket on the electron transfer mechanism in the rate-limiting event may be just as significant for a quantitatively accurate account of the experimentally-measured enantiospecificities. Full article

(This article belongs to the Special Issue Computational Modelling of Enzymatic Reaction Mechanisms)

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3203 KiB

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Modeling of the Reaction Mechanism of Enzymatic Radical C–C Coupling by Benzylsuccinate Synthase

by Maciej Szaleniec and Johann Heider

Int. J. Mol. Sci. 2016, 17(4), 514; https://doi.org/10.3390/ijms17040514 - 7 Apr 2016

Cited by 15 | Viewed by 6714

Abstract

Molecular modeling techniques and density functional theory calculations were performed to study the mechanism of enzymatic radical C–C coupling catalyzed by benzylsuccinate synthase (BSS). BSS has been identified as a glycyl radical enzyme that catalyzes the enantiospecific fumarate addition to toluene initiating its anaerobic metabolism in the denitrifying bacterium Thauera aromatica, and this reaction represents the general mechanism of toluene degradation in all known anaerobic degraders. In this work docking calculations, classical molecular dynamics (MD) simulations, and DFT+D2 cluster modeling was employed to address the following questions: (i) What mechanistic details of the BSS reaction yield the most probable molecular model? (ii) What is the molecular basis of enantiospecificity of BSS? (iii) Is the proposed mechanism consistent with experimental observations, such as an inversion of the stereochemistry of the benzylic protons, syn addition of toluene to fumarate, exclusive production of (R)-benzylsuccinate as a product and a kinetic isotope effect (KIE) ranging between 2 and 4? The quantum mechanics (QM) modeling confirms that the previously proposed hypothetical mechanism is the most probable among several variants considered, although C–H activation and not C–C coupling turns out to be the rate limiting step. The enantiospecificity of the enzyme seems to be enforced by a thermodynamic preference for binding of fumarate in the pro(R) orientation and reverse preference of benzyl radical attack on fumarate in pro(S) pathway which results with prohibitively high energy barrier of the radical quenching. Finally, the proposed mechanism agrees with most of the experimental observations, although the calculated intrinsic KIE from the model (6.5) is still higher than the experimentally observed values (4.0) which suggests that both C–H activation and radical quenching may jointly be involved in the kinetic control of the reaction. Full article

(This article belongs to the Special Issue Computational Modelling of Enzymatic Reaction Mechanisms)

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7592 KiB

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Challenging Density Functional Theory Calculations with Hemes and Porphyrins

by Sam P. De Visser and Martin J. Stillman

Int. J. Mol. Sci. 2016, 17(4), 519; https://doi.org/10.3390/ijms17040519 - 7 Apr 2016

Cited by 25 | Viewed by 9804

Abstract

In this paper we review recent advances in computational chemistry and specifically focus on the chemical description of heme proteins and synthetic porphyrins that act as both mimics of natural processes and technological uses. These are challenging biochemical systems involved in electron transfer as well as biocatalysis processes. In recent years computational tools have improved considerably and now can reproduce experimental spectroscopic and reactivity studies within a reasonable error margin (several kcal·mol⁻¹). This paper gives recent examples from our groups, where we investigated heme and synthetic metal-porphyrin systems. The four case studies highlight how computational modelling can correctly reproduce experimental product distributions, predicted reactivity trends and guide interpretation of electronic structures of complex systems. The case studies focus on the calculations of a variety of spectroscopic features of porphyrins and show how computational modelling gives important insight that explains the experimental spectra and can lead to the design of porphyrins with tuned properties. Full article

(This article belongs to the Special Issue Computational Modelling of Enzymatic Reaction Mechanisms)

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