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Computational Enzymology: Understanding the Properties, Dynamics, and Reactivity of Enzymes

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Computational and Theoretical Chemistry".

Deadline for manuscript submissions: closed (31 October 2019) | Viewed by 17296

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Prof. Dr. James Gauld

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Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON N9B 3P4, Canada
Interests: computational chemistry; quantum mechanics/molecular mechanics; molecular dynamics; docking; catalysis; enzymology; thermochemistry; reaction mechanisms; sulfur biochemistry
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Dear Colleagues,

Enzymes are essential to a vast array of physiological processes critical to the proper functioning and sustainability of cells and organisms. As a result, acomplete understanding of the properties and chemistry of enzymes has long been a goal of researchers. In addition, however, such investigations have the potential to provide: (i) new insights into the underlying fundamental chemical principles involved; (ii) health and medical benefits through elucidating the chemical basis of diseases or therapeutic drug development; as well as (iii) industrially-relevant breakthroughs (e.g., new catalysts).Ongoing developments of new and more powerful computational methods has made computational enzymology an essential tool in our efforts to obtain a complete understanding of enzymes. It can now reliably and accurately model and predict properties and reactions from the atomic to the macroscopic level, at or beyond the limits of experiment. This Special Issue aims to highlight and showcase the ways in which computational enzymology can be applied and used to answer important (bio)chemical questions and challenges.

Dr. James W. Gauld
Guest Editor

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Keywords

Catalysis
Mechanism
Inhibition
Regulation
Thermochemistry
QM/MM
Molecular Dynamics
QM-Cluster

Published Papers (4 papers)

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Research

15 pages, 1653 KiB

Open AccessArticle

Catalytic Hydrolysis Mechanism of Cocaine by Human Carboxylesterase 1: An Orthoester Intermediate Slows Down the Reaction

by Maocai Yan, Zhen Zhang, Zhaoming Liu, Chunyan Zhang, Jingchang Zhang, Shuai Fan and Zhaoyong Yang

Molecules 2019, 24(22), 4057; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24224057 - 09 Nov 2019

Cited by 4 | Viewed by 3481

Abstract

Human carboxylesterase 1 (hCES1) is a major carboxylesterase in the human body and plays important roles in the metabolism of a wide variety of substances, including lipids and drugs, and therefore is attracting more and more attention from areas including lipid metabolism, pharmacokinetics, drug–drug interactions, and prodrug activation. In this work, we studied the catalytic hydrolysis mechanism of hCES1 by the quantum mechanics computation method, using cocaine as a model substrate. Our results support the four-step theory of the esterase catalytic hydrolysis mechanism, in which both the acylation stage and the deacylation stage include two transition states and a tetrahedral intermediate. The roles and cooperation of the catalytic triad, S221, H468, and E354, were also analyzed in this study. Moreover, orthoester intermediates were found in hCES1-catalyzed cocaine hydrolysis reaction, which significantly elevate the free energy barrier and slow down the reaction. Based on this finding, we propose that hCES1 substrates with β-aminocarboxylester structure might form orthoester intermediates in hCES1-catalyzed hydrolysis, and therefore prolong their in vivo half-life. Thus, this study helps to clarify the catalytic mechanism of hCES1 and elucidates important details of its catalytic process, and furthermore, provides important insights into the metabolism of hCES1 substrates and drug designing. Full article

(This article belongs to the Special Issue Computational Enzymology: Understanding the Properties, Dynamics, and Reactivity of Enzymes)

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10 pages, 2659 KiB

Open AccessArticle

Molecular Docking and Dynamics Simulation of Protein β-Tubulin and Antifungal Cyclic Lipopeptides

by Nubia Noemi Cob-Calan, Luz America Chi-Uluac, Filiberto Ortiz-Chi, Daniel Cerqueda-García, Gabriel Navarrete-Vázquez, Esaú Ruiz-Sánchez and Emanuel Hernández-Núñez

Molecules 2019, 24(18), 3387; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24183387 - 18 Sep 2019

Cited by 32 | Viewed by 5785

Abstract

To elucidate interactions between the antifungal cyclic lipopeptides iturin A, fengycin, and surfactin produced by Bacillus bacteria and the microtubular protein β-tubulin in plant pathogenic fungi (Fusarium oxysporum, Colletrotrichum gloeosporioides, Alternaria alternata, and Fusarium solani) in molecular docking and molecular dynamics simulations, we retrieved the structure of tubulin co-crystallized with taxol from the Protein Data Bank (PDB) (ID: 1JFF) and the structure of the cyclic lipopeptides from PubChem (Compound CID: 102287549, 100977820, 10129764). Similarity and homology analyses of the retrieved β-tubulin structure with those of the fungi showed that the conserved domains shared 84% similarity, and the root mean square deviation (RMSD) was less than 2 Å. In the molecular docking studies, within the binding pocket, residues Pro274, Thr276, and Glu27 of β-tubulin were responsible for the interaction with the cyclic lipopeptides. In the molecular dynamics analysis, two groups of ligands were formed based on the number of poses analyzed with respect to the RMSD. Group 1 was made up of 10, 100, and 500 poses with distances 0.080 to 0.092 nm and RMSDs of 0.10 to 0.15 nm. For group 2, consisting of 1000 poses, the initial and final distance was 0.1 nm and the RMSDs were in the range of 0.10 to 0.30 nm. These results suggest that iturin A and fengycin bind with higher affinity than surfactin to β-tubulin. These two lipopeptides may be used as lead compounds to develop new antifungal agents or employed directly as biorational products to control plant pathogenic fungi. Full article

(This article belongs to the Special Issue Computational Enzymology: Understanding the Properties, Dynamics, and Reactivity of Enzymes)

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24 pages, 3699 KiB

Open AccessArticle

Molecular Dynamics Gives New Insights into the Glucose Tolerance and Inhibition Mechanisms on β-Glucosidases

by Leon Sulfierry Corrêa Costa, Diego César Batista Mariano, Rafael Eduardo Oliveira Rocha, Johannes Kraml, Carlos Henrique da Silveira, Klaus Roman Liedl, Raquel Cardoso de Melo-Minardi and Leonardo Henrique Franca de Lima

Molecules 2019, 24(18), 3215; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24183215 - 04 Sep 2019

Cited by 16 | Viewed by 4595

Abstract

β-Glucosidases are enzymes with high importance for many industrial processes, catalyzing the last and limiting step of the conversion of lignocellulosic material into fermentable sugars for biofuel production. However, β-glucosidases are inhibited by high concentrations of the product (glucose), which limits the biofuel production on an industrial scale. For this reason, the structural mechanisms of tolerance to product inhibition have been the target of several studies. In this study, we performed in silico experiments, such as molecular dynamics (MD) simulations, free energy landscape (FEL) estimate, Poisson–Boltzmann surface area (PBSA), and grid inhomogeneous solvation theory (GIST) seeking a better understanding of the glucose tolerance and inhibition mechanisms of a representative GH1 β-glucosidase and a GH3 one. Our results suggest that the hydrophobic residues Y180, W350, and F349, as well the polar one D238 act in a mechanism for glucose releasing, herein called “slingshot mechanism”, dependent also on an allosteric channel (AC). In addition, water activity modulation and the protein loop motions suggest that GH1 β-Glucosidases present an active site more adapted to glucose withdrawal than GH3, in consonance with the GH1s lower product inhibition. The results presented here provide directions on the understanding of the molecular mechanisms governing inhibition and tolerance to the product in β-glucosidases and can be useful for the rational design of optimized enzymes for industrial interests. Full article

(This article belongs to the Special Issue Computational Enzymology: Understanding the Properties, Dynamics, and Reactivity of Enzymes)

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12 pages, 3216 KiB

Open AccessArticle

The Role of Active-Site Residues Phe98, His239, and Arg243 in DNA Binding and in the Catalysis of Human Uracil–DNA Glycosylase SMUG1

by Danila A. Iakovlev, Irina V. Alekseeva, Yury N. Vorobjev, Nikita A. Kuznetsov and Olga S. Fedorova

Molecules 2019, 24(17), 3133; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24173133 - 28 Aug 2019

Cited by 2 | Viewed by 2539

Abstract

Human SMUG1 (hSMUG1) hydrolyzes the N-glycosidic bond of uracil and some uracil lesions formed in the course of epigenetic regulation. Despite the functional importance of hSMUG1 in the DNA repair pathway, the damage recognition mechanism has been elusive to date. In the present study, our objective was to build a model structure of the enzyme–DNA complex of wild-type hSMUG1 and several hSMUG1 mutants containing substitution F98W, H239A, or R243A. Enzymatic activity of these mutant enzymes was examined by polyacrylamide gel electrophoresis analysis of the reaction product formation and pre-steady-state analysis of DNA conformational changes during enzyme–DNA complex formation. It was shown that substitutions F98W and H239A disrupt specific contacts generated by the respective wild-type residues, namely stacking with a flipped out Ura base in the damaged base-binding pocket or electrostatic interactions with DNA in cases of Phe98 and His239, respectively. A loss of the Arg side chain in the case of R243A reduced the rate of DNA bending and increased the enzyme turnover rate, indicating facilitation of the product release step. Full article

(This article belongs to the Special Issue Computational Enzymology: Understanding the Properties, Dynamics, and Reactivity of Enzymes)

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