Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
7.4
4.2
Journals
Molecules
Special Issues
Modeling Enzyme Action—A Themed Honorary Issue to Prof. Fredric M....
molecules-logo
Submit to Molecules Review for Molecules Propose a Special Issue

Journal Menu

► Journal Menu

Journal Browser

► Journal Browser
share announcement

Modeling Enzyme Action—A Themed Honorary Issue to Prof. Fredric M. Menger

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

Deadline for manuscript submissions: closed (15 August 2021) | Viewed by 22972

Special Issue Editor

Prof. Dr. Rafik Karaman

E-Mail Website
Guest Editor
1. Pharmaceutical & Medicinal Chemistry Department, Faculty of Pharmacy, Al-Quds University, Jerusalem P.O. Box 20002, Palestine
2. Department of Sciences, University of Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy
Interests: design and synthesis of anticancer prodrugs with targeting properties determined by the linker’s type; design and synthesis of prodrugs with inefficient bioavailability; design and synthesis of prodrugs for masking the bitter sensation of commonly used drugs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Molecules is pleased to announce a Special Issue dedicated to Fredric M. Menger, an emeritus professor of chemistry at Emory University, to celebrate his outstanding contribution to the synthesis and examination of organic systems and materials with biological importance. Among the projects that have emerged from his research group over the years are the following: (a) naming, synthesizing, and characterizing gemini surfactants; (b) quantitatively formulating the pseudo-phase model of micellar reactions; (c) reconstructing the conventional Hartley micelle model;  (d) devising the 1,4-di-13C NMR method for determining hydrocarbon-chain conformation; (e) using microemulsion systems to destroy chemical warfare agents; (f) applying light microscopy to monitor morphological changes, e.g., budding and birthing, in giant-vesicle membranes; (g) correcting the classical Gibbs analysis of surface tension data; (h) constructing metallo-micelles and combinatorial metallo-polymers as enzyme models; (i) experimentally disproving the orbital steering theory of enzymes; (j) studying aqueous gels of small organic molecules via viscometric methods; (k) determining the kinetics of enzymes dissolved in heptane with water-pools; (l) evaluating the negative rate constant concept; (m) synthesizing delivery systems based on liposomes labile to specific enzymes; (n) introducing the role of distance in enzyme action; and (o) proposing an epigenetic model for the evolution of human intelligence.

The striking efficiency of enzyme catalysis has motivated several organic chemists to unravel enzyme mechanisms by exploring certain intra-molecular reactions, such as enzyme models that proceed faster than their corresponding intermolecular counterparts. This brings about the important question of whether enzyme models have the potential to replace natural enzymes. Today, the consensus is that the catalytic activity of an enzyme is based on the combined effects of catalysis by functional groups and the ability to reroute intermolecular reactions through alternative pathways by which substrates bind to preorganized active sites. Rate acceleration by enzymes can be due to (a) covalently enforced proximity, as in chymotrypsin, (b) non-covalently enforced proximity, as in the catalytic activity of metallo-enzymes, (c) covalently enforced strain, and (d) non-covalently enforced strain, which has been extensively studied in models that mimic the enzyme lysozyme.

The rate constants for a large majority of enzymatic reactions exceed their non-enzymatic bimolecular counterparts by 1010 to 1018 fold. For example, reactions catalyzed by cyclophilin are enhanced by 105 and those by orotidine monophosphatedecarboxylase are enhanced by 1017. The significant rate of acceleration achieved by enzymes is brought about by the binding of the substrate within the confines of the enzyme pocket called the active site. The binding energy of the resulting enzyme–substrate complex is the dominant driving force and the major contributor to catalysis. It is believed that in all enzymatic reactions, binding energy is used to overcome prominent physical and thermodynamic factors that create barriers for the reaction (ΔG). Both, enzymes and intra-molecular processes are similar in that the reacting centers are held together (covalently with intra molecular systems, and non-covalently with enzymes).

In this Special Issue “Modeling Enzyme Action—A Themed Honorary Issue to Prof. Fredric M. Menger”, the various strategies employed in modeling enzyme action will be reported. Both reviews and original research contributions will be accepted.

Prof. Dr. Rafik Karaman
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • enzyme models
  • intramolecular processes
  • enzymes mechanisms
  • mimicking enzymes

Benefits of Publishing in a Special Issue

  • Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
  • Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
  • Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
  • External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
  • e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue polices can be found here.

Published Papers (7 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Editorial

Jump to: Research, Review

9 pages, 203 KiB  
Editorial
An Alternative Molecular View of Evolution: How DNA was Altered over Geological Time
by Fredric M. Menger
Molecules 2020, 25(21), 5081; https://doi.org/10.3390/molecules25215081 - 2 Nov 2020
Cited by 4 | Viewed by 2482
Abstract
Four natural phenomena are cited for their defiance of conventional neo-Darwinian analysis: human intelligence; cat domesticity; the Cambrian explosion; and convergent evolution. 1. Humans are now far more intelligent than needed in their hunting–gathering days >10,000 years ago. 2. Domestic cats evolved from [...] Read more.
Four natural phenomena are cited for their defiance of conventional neo-Darwinian analysis: human intelligence; cat domesticity; the Cambrian explosion; and convergent evolution. 1. Humans are now far more intelligent than needed in their hunting–gathering days >10,000 years ago. 2. Domestic cats evolved from wildcats via major genetic and physical changes, all occurring in less than 12,000 years. 3. The Cambrian explosion refers to the remarkable expansion of species that mystifies evolutionists, as there is a total lack of fossil evidence for precursors of this abundant new life. 4. Convergent evolution often involves formation of complex, multigene traits in two or more species that have no common ancestor. These four evolutionary riddles are discussed in terms of a proposed “preassembly” mechanism in which genes and gene precursors are collected silently and randomly over extensive time periods within huge non-coding sections of DNA. This is followed by epigenetic release of the genes, when the environment so allows, and by natural selection. In neo-Darwinism, macroevolution of complex traits involves multiple mutation/selections, with each of the resulting intermediates being more favorable to the species than the previous one. Preassembly, in contrast, invokes natural selection only after a partially or fully formed trait is already in place. Preassembly does not supplant neo-Darwinism but, instead, supplements neo-Darwinism in those important instances where the classical theory is wanting. Full article
(This article belongs to the Special Issue Modeling Enzyme Action—A Themed Honorary Issue to Prof. Fredric M. Menger)

Research

Jump to: Editorial, Review

18 pages, 1308 KiB  
Article
Towards Predicting Partitioning of Enzymes between Macromolecular Phases: Effects of Polydispersity on the Phase Behavior of Nonadditive Hard Spheres in Solution
by Luka Sturtewagen and Erik van der Linden
Molecules 2022, 27(19), 6354; https://doi.org/10.3390/molecules27196354 - 26 Sep 2022
Cited by 4 | Viewed by 1368
Abstract
The ability to separate enzymes, or cells or viruses, from a mixture is important and can be realized by the incorporation of the mixture into a macromolecular solution. This incorporation may lead to a spontaneous phase separation, with one phase containing the majority [...] Read more.
The ability to separate enzymes, or cells or viruses, from a mixture is important and can be realized by the incorporation of the mixture into a macromolecular solution. This incorporation may lead to a spontaneous phase separation, with one phase containing the majority of one of the species of interest. Inspired by this phenomenon, we studied the theoretical phase behavior of a model system composed of an asymmetric binary mixture of hard spheres, of which the smaller component was monodisperse and the larger component was polydisperse. The interactions were modeled in terms of the second virial coefficient and could be additive hard sphere (HS) or nonadditive hard sphere (NAHS) interactions. The polydisperse component was subdivided into two subcomponents and had an average size ten or three times the size of the monodisperse component. We gave the set of equations that defined the phase diagram for mixtures with more than two components in a solvent. We calculated the theoretical liquid–liquid phase separation boundary for the two-phase separation (the binodal) and three-phase separation, the plait point, and the spinodal. We varied the distribution of the polydisperse component in skewness and polydispersity, and we varied the nonadditivity between the subcomponents as well as between the main components. We compared the phase behavior of the polydisperse mixtures with binary monodisperse mixtures for the same average size and binary monodisperse mixtures for the same effective interaction. We found that when the compatibility between the polydisperse subcomponents decreased, the three-phase separation became possible. The shape and position of the phase boundary was dependent on the nonadditivity between the subcomponents as well as their size distribution. We conclude that it is the phase enriched in the polydisperse component that demixes into an additional phase when the incompatibility between the subcomponents increases. Full article
(This article belongs to the Special Issue Modeling Enzyme Action—A Themed Honorary Issue to Prof. Fredric M. Menger)
►▼ Show Figures

Figure 1

29 pages, 1213 KiB  
Article
Effects of Polydispersity on the Phase Behavior of Additive Hard Spheres in Solution
by Luka Sturtewagen and Erik van der Linden
Molecules 2021, 26(6), 1543; https://doi.org/10.3390/molecules26061543 - 11 Mar 2021
Cited by 5 | Viewed by 1877
Abstract
The ability to separate enzymes, nucleic acids, cells, and viruses is an important asset in life sciences. This can be realised by using their spontaneous asymmetric partitioning over two macromolecular aqueous phases in equilibrium with one another. Such phases can already form while [...] Read more.
The ability to separate enzymes, nucleic acids, cells, and viruses is an important asset in life sciences. This can be realised by using their spontaneous asymmetric partitioning over two macromolecular aqueous phases in equilibrium with one another. Such phases can already form while mixing two different types of macromolecules in water. We investigate the effect of polydispersity of the macromolecules on the two-phase formation. We study theoretically the phase behavior of a model polydisperse system: an asymmetric binary mixture of hard spheres, of which the smaller component is monodisperse and the larger component is polydisperse. The interactions are modelled in terms of the second virial coefficient and are assumed to be additive hard sphere interactions. The polydisperse component is subdivided into sub-components and has an average size ten times the size of the monodisperse component. We calculate the theoretical liquid–liquid phase separation boundary (the binodal), the critical point, and the spinodal. We vary the distribution of the polydisperse component in terms of skewness, modality, polydispersity, and number of sub-components. We compare the phase behavior of the polydisperse mixtures with their concomittant monodisperse mixtures. We find that the largest species in the larger (polydisperse) component causes the largest shift in the position of the phase boundary, critical point, and spinodal compared to the binary monodisperse binary mixtures. The polydisperse component also shows fractionation. The smaller species of the polydisperse component favor the phase enriched in the smaller component. This phase also has a higher-volume fraction compared to the monodisperse mixture. Full article
(This article belongs to the Special Issue Modeling Enzyme Action—A Themed Honorary Issue to Prof. Fredric M. Menger)
►▼ Show Figures

Figure 1

13 pages, 1966 KiB  
Article
Site-Specific Tryptophan Labels Reveal Local Microsecond–Millisecond Motions of Dihydrofolate Reductase
by Morgan B. Vaughn, Chloe Biren, Qun Li, Ashwin Ragupathi and R. Brian Dyer
Molecules 2020, 25(17), 3819; https://doi.org/10.3390/molecules25173819 - 22 Aug 2020
Cited by 1 | Viewed by 2866
Abstract
Many enzymes are known to change conformations during their catalytic cycle, but the role of these protein motions is not well understood. Escherichia coli dihydrofolate reductase (DHFR) is a small, flexible enzyme that is often used as a model system for understanding enzyme [...] Read more.
Many enzymes are known to change conformations during their catalytic cycle, but the role of these protein motions is not well understood. Escherichia coli dihydrofolate reductase (DHFR) is a small, flexible enzyme that is often used as a model system for understanding enzyme dynamics. Recently, native tryptophan fluorescence was used as a probe to study micro- to millisecond dynamics of DHFR. Yet, because DHFR has five native tryptophans, the origin of the observed conformational changes could not be assigned to a specific region within the enzyme. Here, we use DHFR mutants, each with a single tryptophan as a probe for temperature jump fluorescence spectroscopy, to further inform our understanding of DHFR dynamics. The equilibrium tryptophan fluorescence of the mutants shows that each tryptophan is in a different environment and that wild-type DHFR fluorescence is not a simple summation of all the individual tryptophan fluorescence signatures due to tryptophan–tryptophan interactions. Additionally, each mutant exhibits a two-phase relaxation profile corresponding to ligand association/dissociation convolved with associated conformational changes and a slow conformational change that is independent of ligand association and dissociation, similar to the wild-type enzyme. However, the relaxation rate of the slow phase depends on the location of the tryptophan within the enzyme, supporting the conclusion that the individual tryptophan fluorescence dynamics do not originate from a single collective motion, but instead report on local motions throughout the enzyme. Full article
(This article belongs to the Special Issue Modeling Enzyme Action—A Themed Honorary Issue to Prof. Fredric M. Menger)
►▼ Show Figures

Figure 1

Review

Jump to: Editorial, Research

26 pages, 2966 KiB  
Review
The Kynurenine Pathway and Kynurenine 3-Monooxygenase Inhibitors
by Tamera D. Hughes, Osman F. Güner, Emma Carine Iradukunda, Robert S. Phillips and J. Phillip Bowen
Molecules 2022, 27(1), 273; https://doi.org/10.3390/molecules27010273 - 2 Jan 2022
Cited by 34 | Viewed by 5271
Abstract
Under normal physiological conditions, the kynurenine pathway (KP) plays a critical role in generating cellular energy and catabolizing tryptophan. Under inflammatory conditions, however, there is an upregulation of the KP enzymes, particularly kynurenine 3-monooxygenase (KMO). KMO has garnered much attention due to its [...] Read more.
Under normal physiological conditions, the kynurenine pathway (KP) plays a critical role in generating cellular energy and catabolizing tryptophan. Under inflammatory conditions, however, there is an upregulation of the KP enzymes, particularly kynurenine 3-monooxygenase (KMO). KMO has garnered much attention due to its production of toxic metabolites that have been implicated in many diseases and disorders. With many of these illnesses having an inadequate or modest treatment, there exists a need to develop KMO inhibitors that reduce the production of these toxic metabolites. Though prior efforts to find an appropriate KMO inhibitor were unpromising, the development of a KMO crystal structure has provided the opportunity for a rational structure-based design in the development of inhibitors. Therefore, the purpose of this review is to describe the kynurenine pathway, the kynurenine 3-monooxygenase enzyme, and KMO inhibitors and their potential candidacy for clinical use. Full article
(This article belongs to the Special Issue Modeling Enzyme Action—A Themed Honorary Issue to Prof. Fredric M. Menger)
►▼ Show Figures

Figure 1

28 pages, 3385 KiB  
Review
Enzyme Models—From Catalysis to Prodrugs
by Zeinab Breijyeh and Rafik Karaman
Molecules 2021, 26(11), 3248; https://doi.org/10.3390/molecules26113248 - 28 May 2021
Cited by 7 | Viewed by 4679
Abstract
Enzymes are highly specific biological catalysts that accelerate the rate of chemical reactions within the cell. Our knowledge of how enzymes work remains incomplete. Computational methodologies such as molecular mechanics (MM) and quantum mechanical (QM) methods play an important role in elucidating the [...] Read more.
Enzymes are highly specific biological catalysts that accelerate the rate of chemical reactions within the cell. Our knowledge of how enzymes work remains incomplete. Computational methodologies such as molecular mechanics (MM) and quantum mechanical (QM) methods play an important role in elucidating the detailed mechanisms of enzymatic reactions where experimental research measurements are not possible. Theories invoked by a variety of scientists indicate that enzymes work as structural scaffolds that serve to bring together and orient the reactants so that the reaction can proceed with minimum energy. Enzyme models can be utilized for mimicking enzyme catalysis and the development of novel prodrugs. Prodrugs are used to enhance the pharmacokinetics of drugs; classical prodrug approaches focus on alternating the physicochemical properties, while chemical modern approaches are based on the knowledge gained from the chemistry of enzyme models and correlations between experimental and calculated rate values of intramolecular processes (enzyme models). A large number of prodrugs have been designed and developed to improve the effectiveness and pharmacokinetics of commonly used drugs, such as anti-Parkinson (dopamine), antiviral (acyclovir), antimalarial (atovaquone), anticancer (azanucleosides), antifibrinolytic (tranexamic acid), antihyperlipidemia (statins), vasoconstrictors (phenylephrine), antihypertension (atenolol), antibacterial agents (amoxicillin, cephalexin, and cefuroxime axetil), paracetamol, and guaifenesin. This article describes the works done on enzyme models and the computational methods used to understand enzyme catalysis and to help in the development of efficient prodrugs. Full article
(This article belongs to the Special Issue Modeling Enzyme Action—A Themed Honorary Issue to Prof. Fredric M. Menger)
►▼ Show Figures

Figure 1

14 pages, 2427 KiB  
Review
Computational Approaches: An Underutilized Tool in the Quest to Elucidate Radical SAM Dynamics
by Tamra C. Blue and Katherine M. Davis
Molecules 2021, 26(9), 2590; https://doi.org/10.3390/molecules26092590 - 29 Apr 2021
Cited by 5 | Viewed by 3383
Abstract
Enzymes are biological catalysts whose dynamics enable their reactivity. Visualizing conformational changes, in particular, is technically challenging, and little is known about these crucial atomic motions. This is especially problematic for understanding the functional diversity associated with the radical S-adenosyl-L-methionine (SAM) superfamily [...] Read more.
Enzymes are biological catalysts whose dynamics enable their reactivity. Visualizing conformational changes, in particular, is technically challenging, and little is known about these crucial atomic motions. This is especially problematic for understanding the functional diversity associated with the radical S-adenosyl-L-methionine (SAM) superfamily whose members share a common radical mechanism but ultimately catalyze a broad range of challenging reactions. Computational chemistry approaches provide a readily accessible alternative to exploring the time-resolved behavior of these enzymes that is not limited by experimental logistics. Here, we review the application of molecular docking, molecular dynamics, and density functional theory, as well as hybrid quantum mechanics/molecular mechanics methods to the study of these enzymes, with a focus on understanding the mechanistic dynamics associated with turnover. Full article
(This article belongs to the Special Issue Modeling Enzyme Action—A Themed Honorary Issue to Prof. Fredric M. Menger)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-7
Back to TopTop