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  1. Article ; Online: Crystallography and QM/MM Simulations Identify Preferential Binding of Hydrolyzed Carbapenem and Penem Antibiotics to the L1 Metallo-β-Lactamase in the Imine Form.

    Twidale, Rebecca M / Hinchliffe, Philip / Spencer, James / Mulholland, Adrian J

    Journal of chemical information and modeling

    2021  Volume 61, Issue 12, Page(s) 5988–5999

    Abstract: Widespread bacterial resistance to carbapenem antibiotics is an increasing global health concern. Resistance has emerged due to carbapenem-hydrolyzing enzymes, including metallo-β-lactamases (MβLs), but despite their prevalence and clinical importance, ... ...

    Abstract Widespread bacterial resistance to carbapenem antibiotics is an increasing global health concern. Resistance has emerged due to carbapenem-hydrolyzing enzymes, including metallo-β-lactamases (MβLs), but despite their prevalence and clinical importance, MβL mechanisms are still not fully understood. Carbapenem hydrolysis by MβLs can yield alternative product tautomers with the potential to access different binding modes. Here, we show that a combined approach employing crystallography and quantum mechanics/molecular mechanics (QM/MM) simulations allow tautomer assignment in MβL:hydrolyzed antibiotic complexes. Molecular simulations also examine (meta)stable species of alternative protonation and tautomeric states, providing mechanistic insights into β-lactam hydrolysis. We report the crystal structure of the hydrolyzed carbapenem ertapenem bound to the L1 MβL from
    MeSH term(s) Anti-Bacterial Agents/chemistry ; Carbapenems/pharmacology ; Crystallography, X-Ray ; Imines ; Meropenem ; beta-Lactamases/chemistry
    Chemical Substances Anti-Bacterial Agents ; Carbapenems ; Imines ; beta-lactamase L1 (EC 3.5.2.-) ; beta-Lactamases (EC 3.5.2.6) ; Meropenem (FV9J3JU8B1)
    Language English
    Publishing date 2021-10-12
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 190019-5
    ISSN 1549-960X ; 0095-2338
    ISSN (online) 1549-960X
    ISSN 0095-2338
    DOI 10.1021/acs.jcim.1c00663
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1230: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article: Mechanism of covalent binding of ibrutinib to Bruton's tyrosine kinase revealed by QM/MM calculations.

    Voice, Angus T / Tresadern, Gary / Twidale, Rebecca M / van Vlijmen, Herman / Mulholland, Adrian J

    Chemical science

    2021  Volume 12, Issue 15, Page(s) 5511–5516

    Abstract: Ibrutinib is the first covalent inhibitor of Bruton's tyrosine kinase (BTK) to be used in the treatment of B-cell cancers. Understanding the mechanism of covalent inhibition will aid in the design of safer and more selective covalent inhibitors that ... ...

    Abstract Ibrutinib is the first covalent inhibitor of Bruton's tyrosine kinase (BTK) to be used in the treatment of B-cell cancers. Understanding the mechanism of covalent inhibition will aid in the design of safer and more selective covalent inhibitors that target BTK. The mechanism of covalent inhibition in BTK has been uncertain because there is no appropriate residue nearby that can act as a base to deprotonate the cysteine thiol prior to covalent bond formation. We investigate several mechanisms of covalent modification of C481 in BTK by ibrutinib using combined quantum mechanics/molecular mechanics (QM/MM) molecular dynamics reaction simulations. The lowest energy pathway involves direct proton transfer from C481 to the acrylamide warhead in ibrutinib, followed by covalent bond formation to form an enol intermediate. There is a subsequent rate-limiting keto-enol tautomerisation step (Δ
    Language English
    Publishing date 2021-01-28
    Publishing country England
    Document type Journal Article
    ZDB-ID 2559110-1
    ISSN 2041-6539 ; 2041-6520
    ISSN (online) 2041-6539
    ISSN 2041-6520
    DOI 10.1039/d0sc06122k
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Multiscale Workflow for Modeling Ligand Complexes of Zinc Metalloproteins.

    Yang, Zongfan / Twidale, Rebecca M / Gervasoni, Silvia / Suardíaz, Reynier / Colenso, Charlotte K / Lang, Eric J M / Spencer, James / Mulholland, Adrian J

    Journal of chemical information and modeling

    2021  Volume 61, Issue 11, Page(s) 5658–5672

    Abstract: Zinc metalloproteins are ubiquitous, with protein zinc centers of structural and functional importance, involved in interactions with ligands and substrates and often of pharmacological interest. Biomolecular simulations are increasingly prominent in ... ...

    Abstract Zinc metalloproteins are ubiquitous, with protein zinc centers of structural and functional importance, involved in interactions with ligands and substrates and often of pharmacological interest. Biomolecular simulations are increasingly prominent in investigations of protein structure, dynamics, ligand interactions, and catalysis, but zinc poses a particular challenge, in part because of its versatile, flexible coordination. A computational workflow generating reliable models of ligand complexes of biological zinc centers would find broad application. Here, we evaluate the ability of alternative treatments, using (nonbonded) molecular mechanics (MM) and quantum mechanics/molecular mechanics (QM/MM) at semiempirical (DFTB3) and density functional theory (DFT) levels of theory, to describe the zinc centers of ligand complexes of six metalloenzyme systems differing in coordination geometries, zinc stoichiometries (mono- and dinuclear), and the nature of interacting groups (specifically the presence of zinc-sulfur interactions). MM molecular dynamics (MD) simulations can overfavor octahedral geometries, introducing additional water molecules to the zinc coordination shell, but this can be rectified by subsequent semiempirical (DFTB3) QM/MM MD simulations. B3LYP/MM geometry optimization further improved the accuracy of the description of coordination distances, with the overall effectiveness of the approach depending upon factors, including the presence of zinc-sulfur interactions that are less well described by semiempirical methods. We describe a workflow comprising QM/MM MD using DFTB3 followed by QM/MM geometry optimization using DFT (e.g., B3LYP) that well describes our set of zinc metalloenzyme complexes and is likely to be suitable for creating accurate models of zinc protein complexes when structural information is more limited.
    MeSH term(s) Ligands ; Metalloproteins ; Quantum Theory ; Workflow ; Zinc
    Chemical Substances Ligands ; Metalloproteins ; Zinc (J41CSQ7QDS)
    Language English
    Publishing date 2021-11-08
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 190019-5
    ISSN 1549-960X ; 0095-2338
    ISSN (online) 1549-960X
    ISSN 0095-2338
    DOI 10.1021/acs.jcim.1c01109
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1230: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article: Current-Generating Double-Layer Shoe with a Porous Sole: Ion Transport Matters

    Kornyshev, Alexei A / Twidale Rebecca M / Kolomeisky Anatoly B

    The Journal of Physical Chemistry C. 2017 Apr. 13, v. 121, no. 14

    2017  

    Abstract: Generating electrical current from mechanically forced variation of the contact area of electrode/electrolyte interface underpins one of the scenarios of harvesting electrical current from walking. We develop here theory of an electrical shoe with a ... ...

    Abstract Generating electrical current from mechanically forced variation of the contact area of electrode/electrolyte interface underpins one of the scenarios of harvesting electrical current from walking. We develop here theory of an electrical shoe with a porous sole with an account of both convection of the liquid electrolyte under pressure and ion migration with transmission-line-type charging of electrical double layer at the pore walls. We show here that ion transport limitations can dramatically reduce the generated current and power density. The developed theory describes the time dependence of the generated current and reveals its dependence on the main operation parameters, the amplitudes of oscillating pressure and frequency, in relation to the system parameters.
    Keywords convection ; electric current ; electrodes ; electrolytes ; physical chemistry ; walking
    Language English
    Dates of publication 2017-0413
    Size p. 7584-7595.
    Publishing place American Chemical Society
    Document type Article
    ISSN 1932-7455
    DOI 10.1021%2Facs.jpcc.6b11385
    Database NAL-Catalogue (AGRICOLA)

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  5. Article ; Online: Charge migration in polycyclic norbornadiene cations: Winning the race against decoherence.

    Jenkins, Andrew J / Vacher, Morgane / Twidale, Rebecca M / Bearpark, Michael J / Robb, Michael A

    The Journal of chemical physics

    2016  Volume 145, Issue 16, Page(s) 164103

    Abstract: The observation of electronic motion remains a key target in the development of the field of attoscience. However, systems in which long-lived oscillatory charge migration may be observed must be selected carefully, particularly because it has been shown ...

    Abstract The observation of electronic motion remains a key target in the development of the field of attoscience. However, systems in which long-lived oscillatory charge migration may be observed must be selected carefully, particularly because it has been shown that nuclear spatial delocalization leads to a loss of coherent electron density oscillations. Here we demonstrate electron dynamics in norbornadiene and extended systems where the hole density migrates between two identical chromophores. By studying the effect of nuclear motion and delocalization in these example systems, we present the physical properties that must be considered in candidate molecules in which to observe electron dynamics. Furthermore, we also show a key contribution to nuclear delocalization arises from motion in the branching plane of the cation. For the systems studied, the dephasing time increases with system size while the energy gap between states, and therefore the frequency of the density oscillation, decreases with size (obeying a simple exponential dependence on the inter-chromophore distance). We present a system that balances these two effects and shows several complete oscillations in the spin density before dephasing occurs.
    Language English
    Publishing date 2016-10-28
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3113-6
    ISSN 1089-7690 ; 0021-9606
    ISSN (online) 1089-7690
    ISSN 0021-9606
    DOI 10.1063/1.4965436
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Bonn / Germany

    Z 4' 49/16: Show issues

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  6. Article: Discovery of SARS-CoV-2 M

    Chan, H T Henry / Moesser, Marc A / Walters, Rebecca K / Malla, Tika R / Twidale, Rebecca M / John, Tobias / Deeks, Helen M / Johnston-Wood, Tristan / Mikhailov, Victor / Sessions, Richard B / Dawson, William / Salah, Eidarus / Lukacik, Petra / Strain-Damerell, Claire / Owen, C David / Nakajima, Takahito / Świderek, Katarzyna / Lodola, Alessio / Moliner, Vicent /
    Glowacki, David R / Spencer, James / Walsh, Martin A / Schofield, Christopher J / Genovese, Luigi / Shoemark, Deborah K / Mulholland, Adrian J / Duarte, Fernanda / Morris, Garrett M

    Chemical science

    2021  Volume 12, Issue 41, Page(s) 13686–13703

    Abstract: The main protease ( ... ...

    Abstract The main protease (M
    Language English
    Publishing date 2021-09-06
    Publishing country England
    Document type Journal Article
    ZDB-ID 2559110-1
    ISSN 2041-6539 ; 2041-6520
    ISSN (online) 2041-6539
    ISSN 2041-6520
    DOI 10.1039/d1sc03628a
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Discovery of SARS-CoV-2 Mpro Peptide Inhibitors from Modelling Substrate and Ligand Binding

    Chan, H. T. Henry / Moesser, Marc A. / Walters, Rebecca K. / Malla, Tika R. / Twidale, Rebecca M. / John, Tobias / Deeks, Helen M. / Johnston-Wood, Tristan / Mikhailov, Victor / Sessions, Richard B. / Dawson, William / Salah, Eidarus / Lukacik, Petra / Strain-Damerell, Claire / Owen, David / Nakajima, Takahito / Swiderek, Katarzyna / Lodola, Alessio / Moliner, Vicent /
    Glowacki, David R. / Walsh, Martin A. / Schofield, Christopher J. / Genovese, Luigi / Shoemark, Deborah / Mulholland, Adrian J. / Duarte, Fernanda / Morris, Garrett M.

    bioRxiv

    Abstract: The main protease (Mpro) of SARS-CoV-2 is central to its viral lifecycle and is a promising drug target, but little is known concerning structural aspects of how it binds to its 11 natural cleavage sites. We used biophysical and crystallographic data and ...

    Abstract The main protease (Mpro) of SARS-CoV-2 is central to its viral lifecycle and is a promising drug target, but little is known concerning structural aspects of how it binds to its 11 natural cleavage sites. We used biophysical and crystallographic data and an array of classical molecular mechanics and quantum mechanical techniques, including automated docking, molecular dynamics (MD) simulations, linear-scaling DFT, QM/MM, and interactive MD in virtual reality, to investigate the molecular features underlying recognition of the natural Mpro substrates. Analyses of the subsite interactions of modelled 11-residue cleavage site peptides, ligands from high-throughput crystallography, and designed covalently binding inhibitors were performed. Modelling studies reveal remarkable conservation of hydrogen bonding patterns of the natural Mpro substrates, particularly on the N-terminal side of the scissile bond. They highlight the critical role of interactions beyond the immediate active site in recognition and catalysis, in particular at the P2/S2 sites. The binding modes of the natural substrates, together with extensive interaction analyses of inhibitor and fragment binding to Mpro, reveal new opportunities for inhibition. Building on our initial Mpro-substrate models, computational mutagenesis scanning was employed to design peptides with improved affinity and which inhibit Mpro competitively. The combined results provide new insight useful for the development of Mpro inhibitors.
    Keywords covid19
    Language English
    Publishing date 2021-06-19
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2021.06.18.446355
    Database COVID19

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