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Article ; Online: Simulating Electron Transfer Reactions in Solution: Radical-Polar Crossover.

Skinner, Kevin C / Kammeraad, Josh A / Wymore, Troy / Narayan, Alison R H / Zimmerman, Paul M

The journal of physical chemistry. B

2023 Volume 127, Issue 47, Page(s) 10097–10107

Abstract: Single-electron transfer (SET) promotes a wide variety of interesting chemical transformations, but modeling of SET requires a careful treatment of electronic and solvent effects to give meaningful insight. Therefore, a combined constrained density ... ...

Abstract	Single-electron transfer (SET) promotes a wide variety of interesting chemical transformations, but modeling of SET requires a careful treatment of electronic and solvent effects to give meaningful insight. Therefore, a combined constrained density functional theory and molecular mechanics (CDFT/MM) tool is introduced specifically for SET-initiated reactions. Mechanisms for two radical-polar crossover reactions involving the organic electron donors tetrakis(dimethylamino)ethylene (TDAE) and tetrathiafulvalene (TTF) were studied with the new tool. An unexpected tertiary radical intermediate within the TDAE system was identified, relationships between kinetics and substitution in the TTF system were explained, and the impact of the solvent environments on the TDAE and TTF reactions were examined. The results highlight the need for including solvent dynamics when quantifying SET kinetics and thermodynamics, as a free energy difference of >20 kcal/mol was observed. Overall, the new method informs mechanistic analysis of SET-initiated reactions and therefore is envisioned to be useful for studying reactions in the condensed phase.
Language	English
Publishing date	2023-11-17
Publishing country	United States
Document type	Journal Article
ISSN	1520-5207
ISSN (online)	1520-5207
DOI	10.1021/acs.jpcb.3c06120
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Article ; Online: Deciphering the evolution of flavin-dependent monooxygenase stereoselectivity using ancestral sequence reconstruction.

Chiang, Chang-Hwa / Wymore, Troy / Rodríguez Benítez, Attabey / Hussain, Azam / Smith, Janet L / Brooks, Charles L / Narayan, Alison R H

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 15, Page(s) e2218248120

Abstract: Controlling the selectivity of a reaction is critical for target-oriented synthesis. Accessing complementary selectivity profiles enables divergent synthetic strategies, but is challenging to achieve in biocatalytic reactions given enzymes' innate ... ...

Abstract	Controlling the selectivity of a reaction is critical for target-oriented synthesis. Accessing complementary selectivity profiles enables divergent synthetic strategies, but is challenging to achieve in biocatalytic reactions given enzymes' innate preferences of a single selectivity. Thus, it is critical to understand the structural features that control selectivity in biocatalytic reactions to achieve tunable selectivity. Here, we investigate the structural features that control the stereoselectivity in an oxidative dearomatization reaction that is key to making azaphilone natural products. Crystal structures of enantiocomplementary biocatalysts guided the development of multiple hypotheses centered on the structural features that control the stereochemical outcome of the reaction; however, in many cases, direct substitutions of active site residues in natural proteins led to inactive enzymes. Ancestral sequence reconstruction (ASR) and resurrection were employed as an alternative strategy to probe the impact of each residue on the stereochemical outcome of the dearomatization reaction. These studies suggest that two mechanisms are active in controlling the stereochemical outcome of the oxidative dearomatization reaction: one involving multiple active site residues in AzaH and the other dominated by a single Phe to Tyr switch in TropB and AfoD. Moreover, this study suggests that the flavin-dependent monooxygenases (FDMOs) adopt simple and flexible strategies to control stereoselectivity, which has led to stereocomplementary azaphilone natural products produced by fungi. This paradigm of combining ASR and resurrection with mutational and computational studies showcases sets of tools for understanding enzyme mechanisms and provides a solid foundation for future protein engineering efforts.
MeSH term(s)	Mixed Function Oxygenases/metabolism ; Oxidation-Reduction ; Flavins/metabolism ; Proteins/metabolism ; Biocatalysis ; Organic Chemicals ; Biological Products/chemistry
Chemical Substances	Mixed Function Oxygenases (EC 1.-) ; Flavins ; Proteins ; Organic Chemicals ; Biological Products
Language	English
Publishing date	2023-04-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2218248120
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Article: Capturing the Catalytic Proton of Dihydrofolate Reductase: Implications for General Acid-Base Catalysis.

Wan, Qun / Bennett, Brad C / Wymore, Troy / Li, Zhihong / Wilson, Mark A / Brooks, Charles L / Langan, Paul / Kovalevsky, Andrey / Dealwis, Chris G

ACS catalysis

2021 Volume 11, Issue 9, Page(s) 5873–5884

Abstract: Acid-base catalysis, which involves one or more proton transfer reactions, is a chemical mechanism commonly employed by many enzymes. The molecular basis for catalysis is often derived from structures determined at the optimal pH for enzyme activity. ... ...

Abstract	Acid-base catalysis, which involves one or more proton transfer reactions, is a chemical mechanism commonly employed by many enzymes. The molecular basis for catalysis is often derived from structures determined at the optimal pH for enzyme activity. However, direct observation of protons from experimental structures is quite difficult; thus, a complete mechanistic description for most enzymes remains lacking. Dihydrofolate reductase (DHFR) exemplifies general acid-base catalysis, requiring hydride transfer and protonation of its substrate, DHF, to form the product, tetrahydrofolate (THF). Previous X-ray and neutron crystal structures coupled with theoretical calculations have proposed that solvent mediates the protonation step. However, visualization of a proton transfer has been elusive. Based on a 2.1 Å resolution neutron structure of a pseudo-Michaelis complex of
Language	English
Publishing date	2021-04-28
Publishing country	United States
Document type	Journal Article
ISSN	2155-5435
ISSN	2155-5435
DOI	10.1021/acscatal.1c00417
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Article ; Online: A reaction pathway to compound 0 intermediates in oxy-myoglobin through interactions with hydrogen sulfide and His64.

Rodriguez-Mackenzie, Angel D / Arbelo-Lopez, Hector D / Wymore, Troy / Lopez-Garriga, Juan

Journal of molecular graphics & modelling

2019 Volume 94, Page(s) 107465

Abstract: Myoglobin (Mb) binds oxygen with high affinity as a low spin singlet complex and thus functions as an oxygen storage protein. Yet, hybrid Density Functional Theory/Molecular Mechanical (DFT/MM) calculations of oxy-Mb models predict that the ... ...

Abstract	Myoglobin (Mb) binds oxygen with high affinity as a low spin singlet complex and thus functions as an oxygen storage protein. Yet, hybrid Density Functional Theory/Molecular Mechanical (DFT/MM) calculations of oxy-Mb models predict that the O
MeSH term(s)	Catalytic Domain ; Hydrogen Peroxide ; Hydrogen Sulfide ; Myoglobin ; Oxygen
Chemical Substances	Myoglobin ; Hydrogen Peroxide (BBX060AN9V) ; Oxygen (S88TT14065) ; Hydrogen Sulfide (YY9FVM7NSN)
Language	English
Publishing date	2019-10-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1396450-1
ISSN	1873-4243 ; 1093-3263
ISSN (online)	1873-4243
ISSN	1093-3263
DOI	10.1016/j.jmgm.2019.107465
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Zs.A 3491: Show issues

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Article: From Molecular Phylogenetics to Quantum Chemistry: Discovering Enzyme Design Principles through Computation.

Wymore, Troy / Brooks, Charles L

Computational and structural biotechnology journal

2012 Volume 2, Page(s) e201209018

Language	English
Publishing date	2012-11-30
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2694435-2
ISSN	2001-0370
ISSN	2001-0370
DOI	10.5936/csbj.201209018
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Article: Hydroxyl Radical-Coupled Electron-Transfer Mechanism of Flavin-Dependent Hydroxylases

Tweedy, Sara E / Rodríguez Benítez, Attabey / Narayan, Alison R. H / Zimmerman, Paul M / Brooks, Charles L / Wymore, Troy

Journal of physical chemistry. 2019 Sept. 05, v. 123, no. 38

2019

Abstract: Class A flavin-dependent hydroxylases (FdHs) catalyze the hydroxylation of organic compounds in a site- and stereoselective manner. In stark contrast, conventional synthetic routes require environmentally hazardous reagents and give modest yields. Thus, ... ...

Abstract	Class A flavin-dependent hydroxylases (FdHs) catalyze the hydroxylation of organic compounds in a site- and stereoselective manner. In stark contrast, conventional synthetic routes require environmentally hazardous reagents and give modest yields. Thus, understanding the detailed mechanism of this class of enzymes is essential to their rational manipulation for applications in green chemistry and pharmaceutical production. Both electrophilic substitution and radical intermediate mechanisms have been proposed as interpretations of FdH hydroxylation rates and optical spectra. While radical mechanistic steps are often difficult to examine directly, modern quantum chemistry calculations combined with statistical mechanical approaches can yield detailed mechanistic models providing insights that can be used to differentiate reaction pathways. In the current work, we report quantum mechanical/molecular mechanical (QM/MM) calculations on the fungal TropB enzyme that shows an alternative reaction pathway in which hydroxylation through a hydroxyl radical-coupled electron-transfer mechanism is significantly favored over electrophilic substitution. Furthermore, QM/MM calculations on several modified flavins provide a more consistent interpretation of the experimental trends in the reaction rates seen experimentally for a related enzyme, para-hydroxybenzoate hydroxylase. These calculations should guide future enzyme and substrate design strategies and broaden the scope of biological spin chemistry.
Keywords	Lewis acids ; electron transfer ; enzymes ; flavins ; fungi ; green chemistry ; hydroxylation ; mechanistic models ; physical chemistry ; quantum mechanics ; stereoselectivity
Language	English
Dates of publication	2019-0905
Size	p. 8065-8073.
Publishing place	American Chemical Society
Document type	Article
ISSN	1520-5207
DOI	10.1021/acs.jpcb.9b08178
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Visualizing Tetrahedral Oxyanion Bound in HIV-1 Protease Using Neutrons: Implications for the Catalytic Mechanism and Drug Design.

Kumar, Mukesh / Mandal, Kalyaneswar / Blakeley, Matthew P / Wymore, Troy / Kent, Stephen B H / Louis, John M / Das, Amit / Kovalevsky, Andrey

ACS omega

2020 Volume 5, Issue 20, Page(s) 11605–11617

Abstract: HIV-1 protease is indispensable for virus propagation and an important therapeutic target for antiviral inhibitors to treat AIDS. As such inhibitors are transition-state mimics, a detailed understanding of the enzyme mechanism is crucial for the ... ...

Abstract	HIV-1 protease is indispensable for virus propagation and an important therapeutic target for antiviral inhibitors to treat AIDS. As such inhibitors are transition-state mimics, a detailed understanding of the enzyme mechanism is crucial for the development of better anti-HIV drugs. Here, we used room-temperature joint X-ray/neutron crystallography to directly visualize hydrogen atoms and map hydrogen bonding interactions in a protease complex with peptidomimetic inhibitor KVS-1 containing a reactive nonhydrolyzable ketomethylene isostere, which, upon reacting with the catalytic water molecule, is converted into a tetrahedral intermediate state, KVS-1
Language	English
Publishing date	2020-05-14
Publishing country	United States
Document type	Journal Article
ISSN	2470-1343
ISSN (online)	2470-1343
DOI	10.1021/acsomega.0c00835
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Article: A Distal Disulfide Bridge in OXA-1 Î²-Lactamase Stabilizes the Catalytic Center and Alters the Dynamics of the Specificity Determining Î© Loop

Simakov, Nikolay / Leonard David A / Smith Jeremy C / Wymore Troy / Szarecka Agnieszka

Journal of physical chemistry. 2017 Apr. 20, v. 121, no. 15

2017

Abstract: Widespread antibiotic resistance, particularly when mediated by broad-spectrum Î²-lactamases, has major implications for public health. Substitutions in the active site often allow broad-spectrum enzymes to accommodate diverse types of Î²-lactams. ... ...

Abstract	Widespread antibiotic resistance, particularly when mediated by broad-spectrum Î²-lactamases, has major implications for public health. Substitutions in the active site often allow broad-spectrum enzymes to accommodate diverse types of Î²-lactams. Substitutions observed outside the active site are thought to compensate for the loss of thermal stability. The OXA-1 clade of class D Î²-lactamases contains a pair of conserved cysteines located outside the active site that forms a disulfide bond in the periplasm. Here, the effect of the distal disulfide bond on the structure and dynamics of OXA-1 was investigated via 4 Î¼s molecular dynamics simulations. The results reveal that the disulfide promotes the preorganized orientation of the catalytic residues and affects the conformation of the functionally important Î© loop. Furthermore, principal component analysis reveals differences in the global dynamics between the oxidized and reduced forms, especially in the motions involving the Î© loop. A dynamical network analysis indicates that, in the oxidized form, in addition to its role in ligand binding, the KTG family motif is a central hub of the global dynamics. As activity of OXA-1 has been measured only in the reduced form, we suggest that accurate assessment of its functional profile would require oxidative conditions mimicking periplasm.
Keywords	active sites ; antibiotic resistance ; beta-lactamase ; beta-lactams ; disulfide bonds ; ligands ; molecular dynamics ; principal component analysis ; public health ; thermal stability
Language	English
Dates of publication	2017-0420
Size	p. 3285-3296.
Publishing place	American Chemical Society
Document type	Article
ISSN	1520-5207
DOI	10.1021%2Facs.jpcb.6b07884
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Article ; Online: Productive reorientation of a bound oxime reactivator revealed in room temperature X-ray structures of native and VX-inhibited human acetylcholinesterase.

Gerlits, Oksana / Kong, Xiaotian / Cheng, Xiaolin / Wymore, Troy / Blumenthal, Donald K / Taylor, Palmer / Radić, Zoran / Kovalevsky, Andrey

The Journal of biological chemistry

2019 Volume 294, Issue 27, Page(s) 10607–10618

Abstract: Exposure to organophosphorus compounds (OPs) may be fatal if untreated, and a clear and present danger posed by nerve agent OPs has become palpable in recent years. OPs inactivate acetylcholinesterase (AChE) by covalently modifying its catalytic serine. ... ...

Abstract	Exposure to organophosphorus compounds (OPs) may be fatal if untreated, and a clear and present danger posed by nerve agent OPs has become palpable in recent years. OPs inactivate acetylcholinesterase (AChE) by covalently modifying its catalytic serine. Inhibited AChE cannot hydrolyze the neurotransmitter acetylcholine leading to its build-up at the cholinergic synapses and creating an acute cholinergic crisis. Current antidotes, including oxime reactivators that attack the OP-AChE conjugate to free the active enzyme, are inefficient. Better reactivators are sought, but their design is hampered by a conformationally rigid portrait of AChE extracted exclusively from 100K X-ray crystallography and scarcity of structural knowledge on human AChE (hAChE). Here, we present room temperature X-ray structures of native and VX-phosphonylated hAChE with an imidazole-based oxime reactivator, RS-170B. We discovered that inhibition with VX triggers substantial conformational changes in bound RS-170B from a "nonproductive" pose (the reactive aldoxime group points away from the VX-bound serine) in the reactivator-only complex to a "semi-productive" orientation in the VX-modified complex. This observation, supported by concurrent molecular simulations, suggested that the narrow active-site gorge of hAChE may be significantly more dynamic than previously thought, allowing RS-170B to reorient inside the gorge. Furthermore, we found that small molecules can bind in the choline-binding site hindering approach to the phosphorous of VX-bound serine. Our results provide structural and mechanistic perspectives on the reactivation of OP-inhibited hAChE and demonstrate that structural studies at physiologically relevant temperatures can deliver previously overlooked insights applicable for designing next-generation antidotes.
MeSH term(s)	Acetylcholinesterase/chemistry ; Acetylcholinesterase/genetics ; Acetylcholinesterase/metabolism ; Binding Sites ; Catalytic Domain ; Cholinesterase Inhibitors/chemistry ; Cholinesterase Inhibitors/metabolism ; Crystallography, X-Ray ; Density Functional Theory ; Humans ; Molecular Dynamics Simulation ; Organothiophosphorus Compounds/chemistry ; Organothiophosphorus Compounds/metabolism ; Oximes/chemistry ; Oximes/metabolism ; Recombinant Proteins/biosynthesis ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Temperature
Chemical Substances	Cholinesterase Inhibitors ; Organothiophosphorus Compounds ; Oximes ; Recombinant Proteins ; VX (9A4381183B) ; Acetylcholinesterase (EC 3.1.1.7)
Language	English
Publishing date	2019-05-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.RA119.008725
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Article ; Online: Hydroxyl Radical-Coupled Electron-Transfer Mechanism of Flavin-Dependent Hydroxylases.

Tweedy, Sara E / Rodríguez Benítez, Attabey / Narayan, Alison R H / Zimmerman, Paul M / Brooks, Charles L / Wymore, Troy

The journal of physical chemistry. B

2019 Volume 123, Issue 38, Page(s) 8065–8073

Abstract	Class A flavin-dependent hydroxylases (FdHs) catalyze the hydroxylation of organic compounds in a site- and stereoselective manner. In stark contrast, conventional synthetic routes require environmentally hazardous reagents and give modest yields. Thus, understanding the detailed mechanism of this class of enzymes is essential to their rational manipulation for applications in green chemistry and pharmaceutical production. Both electrophilic substitution and radical intermediate mechanisms have been proposed as interpretations of FdH hydroxylation rates and optical spectra. While radical mechanistic steps are often difficult to examine directly, modern quantum chemistry calculations combined with statistical mechanical approaches can yield detailed mechanistic models providing insights that can be used to differentiate reaction pathways. In the current work, we report quantum mechanical/molecular mechanical (QM/MM) calculations on the fungal TropB enzyme that shows an alternative reaction pathway in which hydroxylation through a hydroxyl radical-coupled electron-transfer mechanism is significantly favored over electrophilic substitution. Furthermore, QM/MM calculations on several modified flavins provide a more consistent interpretation of the experimental trends in the reaction rates seen experimentally for a related enzyme,
MeSH term(s)	4-Hydroxybenzoate-3-Monooxygenase/chemistry ; 4-Hydroxybenzoate-3-Monooxygenase/metabolism ; Bacteria/enzymology ; Bacterial Proteins/chemistry ; Bacterial Proteins/metabolism ; Biocatalysis ; Density Functional Theory ; Electron Transport ; Hydroxyl Radical/chemistry ; Hydroxyl Radical/metabolism ; Hydroxylation ; Molecular Dynamics Simulation
Chemical Substances	Bacterial Proteins ; Hydroxyl Radical (3352-57-6) ; 4-Hydroxybenzoate-3-Monooxygenase (EC 1.14.13.2)
Language	English
Publishing date	2019-09-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	1520-5207
ISSN (online)	1520-5207
DOI	10.1021/acs.jpcb.9b08178
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