Virtual Winter School on Computational Chemistry

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QM/MM

  • A bottom-up approach towards the design of molecular electronic devices

    Speaker: Dr Mercedes Alonso
    Institute: VU Brussels
    Country: Belgium
    Speaker Link: https://we.vub.ac.be/~algc/algc_new/alonsomresearch.html

    Mercedes Alonso

    General Chemistry Department (ALGC), Vrije Universiteit Brussel (VUB), Pleinlaan 2, Brussels, Belgium

    Creating functional nanoscale devices using single molecules as active electronic components is the ultimate goal of the field of molecular electronics. Besides their potential to meet the growing demand for miniaturization of electronics, molecular electronics opens up the possibility of devices with novel, unforeseen functionalities beyond silicon-based technologies, such as molecular switches. Through a bottom-up quantum chemistry approach, we have shown that expanded porphyrins are flexible enough to switch between different π-conjugation topologies encoding distinct electronic properties and aromaticity.[1]Since these topology/aromaticity switches can be induced by different external stimuli,[2]these macrocycles represent a unique platform to develop molecular switches for different nanoelectronic applications.

    The first application involves the conductance switching in molecular junctions through aromaticity and topology changes. In this regard, the electron transport properties of the different states of the switches were carefully investigated with the non-equilibrium Green´s function formalism in combination with density functional theory for various configurations of the gold contacts.[3]Our findings reveal that the negative relationship between conductance and molecular aromaticity or polarizability does not hold for most of the configurations of the molecular junctions, so we devise new selection rules to predict the occurrence of quantum interference around the Fermi level for Hückel and Möbius systems.[4]A second application concerns the design of bithermoelectric switches, an entirely new class of switches that revert the direction of the heat and /or charge transport. Our in-house calculations reveal that the Hückel-Möbius topology switch in heptaphyrins causes the Seedbeck coefficient or thermopower to change considerably from +50 mV/K to -40 mV/K.[5]Finally, the mechanical activation of this novel type of switches is explored for the first time, leading to a straightforward approach based on distance matrices for the selection of pulling scenarios that promote either the Hückel or the Möbius topology.[6] Overall, our work demonstrates how the concept of aromaticity and molecular topology can be exploited to create a novel type of efficient switching devices.[7]

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    Figure 1.A bottom-up quantum chemical approach to design efficient nanoscale devices.

    Recording:

    Video is available only for registered users.

    References

    [1] M. Alonso, P. Geerlings, F. De Proft, Chem. Eur. J. 2013, 19, 1617.

    [2] M. Alonso, B. Pinter, P. Geerlings, F. De Proft, Chem. Eur. J2015, 21, 17631; T. Woller, J. Contreras-García, P. Geerlings, F. De Proft, M. Alonso, Phys. Chem. Chem. Phys. 2016, 18, 11885;

    [3] T. Stuyver, F. De Proft, P. Geerlings, M. Perrin, M. Alonso, J. Am. Chem. Soc.2018, 140, 1313.

    [4] T. Stuyver, S. Fias, P. Geerlings, F. De Proft, M. Alonso, J. Phys. Chem. C2018, 122, 19482.

    [5] T. Stuyver, P. Geerlings, F. De Proft, M. Alonso, J. Phys. Chem. C2018, 122, 24436.

    [6] T. Bettens, M. Hoffmann, M. Alonso, P. Geerlings, A. Dreuw, F. De Proft, Chem. Eur. J. 2021, ASAP.

    [7] Woller, T.; Geerlings, P.; De Proft, F.; Champagne, B.; Alonso, M. J. Phys. Chem. C2019, 123, 7318.

  • Computational Tools for Covalent Drug Design

    Speaker: Professor György M Keserű
    Institute: Research Center for Natural Sciences
    Country: Hungary
    Speaker Link: http://medchem.ttk.hu/index.html
    Time: 11:00 CET 22-Feb-22

    Professor György M Keserű

    Medicinal Chemistry, Research Center for Natural Sciences, Budapest, Hungary

    Covalent drugs are electrophilic molecules that bound to the target protein by forming covalent bond with the targeted nucleophilic residue at the binding site. Formerly, covalent inhibitors were typically filtered out in drug discovery programs due to the risk of off-target activity attributed to their reactivity. Few compounds acting by covalent mechanism of action were discovered serendipitously. However, a paradigm change has occurred around the millennium owing to the recognition of distinct therapeutic advantages of covalent inhibition that include potentially full target occupancy and long-action, decoupling pharmacodynamics from pharmacokinetics. Therefore, the rational design of targeted covalent inhibitors (TCIs) has gained increased attention.

    The binding of covalent inhibitors follows a two-step mechanism including the first non-covalent binding stage that is the molecular recognition of the non-covalent scaffold. Then the electrophilic functionality of the inhibitor, called warhead reacts with the targeted nucleophilic sidechain of the protein. Here I would focus both steps at two different levels. First I discuss virtual screening applications that allow the prioritization of compounds for experimental testing. After the evaluation of available covalent docking tools [1] we developed new methodologies that allow warhead independent docking of potential covalent inhibitors [2-4]. Next I turned to the accurate prediction of the binding free energy of covalent inhibitors by QM/MM calculations [5]. This approach allows the investigation of the molecular mechanism of action that together with the thermodynamic characterisation facilitate the design of potent covalent inhibitors [6,7].

    Recording:

    Video is available only for registered users.

    References:

    1. Andrea Scarpino, Gyorgy G Ferenczy and György M Keserű:Comparative Evaluation of Covalent Docking Tools Journal of Chemical Information and Modeling201858 (7), 1441-1458.
    2. Andrea Scarpino, László Petri, Damijan Knez, Tímea Imre, Péter Ábrányi-Balogh, György G. Ferenczy, Stanislav Gobec and György M. Keserű:WIDOCK: a reactive docking protocol for virtual screening of covalent inhibitors Journal of Computer-Aided Molecular Design2021, 35, 223–244.
    3. Andrea Scarpino, György G. Ferenczy, György M. Keserű:Binding Mode Prediction and Virtual Screening Applications by Covalent Docking In: Protein-Ligand Interactions and Drug Design (ed. Flavio Ballante), Springer, 2021, pp. 73-88.
    4. Moira Rachman, Andrea Scarpino, Dávid Bajusz, Gyula Pálfy, István Vida, András Perczel, Xavier Barril, György M Keserű:DUckCov: a Dynamic Undocking‐based Virtual Screening Protocol for Covalent Binders ChemMedChem201914, 1011-1021. 
    5. Levente M. Mihalovits, György G. Ferenczy, György M. Keserű:The role of quantum chemistry in covalent inhibitor design International Journal of Quantum Chemistry20211-17
    6. Levente M. Mihalovits, György G. Ferenczy, György M. Keserű:Affinity and Selectivity Assessment of Covalent Inhibitors by Free Energy Calculations Journal of Chemical Information and Modeling202060 (12), 6579-6594.
    7. Levente M. Mihalovits, György G. Ferenczy, György M. Keserű:Mechanistic and thermodynamic characterization of oxathiazolones as potent and selective covalent immunoproteasome inhibitors Computational and Structural Biotechnology Journal202119, 4486-4496.
  • Simulating Two-Dimensional Electronic Spectra

    Speaker: Professor Ivan Rivalta
    Institute: University of Bologna
    Country: Italy
    Speaker Link: https://www.unibo.it/sitoweb/i.rivalta/cv-en

    Professor Ivan Rivalta

    Dipartimento di Chimica Industriale “Toso Montanari”, Università di Bologna, Bologna, Italy

    Laboratoire de Chimie UMR 5182, École Normale Supérieure de Lyon, CNRS, UCBL, Lyon, France

    Two-dimensional electronic spectroscopy (2DES) is a developing multidimensional technique based on ultrashort laser pulses used to track electronic transitions in complex systems with femtosecond spectral and time resolution. 2DES in the ultraviolet (2DUV) can be used to investigate structure, conformation dynamics, energy transfer, and chemical/photochemical reactivity in a wide range of systems in physical chemistry, energy sciences and biophysics. The interpretation of 2D electronic spectra is challenging and computational modeling is required to disentangle the congested information contained in the nonlinear optical response of the sample. In this presentation, the 2DES technique and its theoretical basis are introduced along with an illustration of the computational tools and protocols that we developed to perform first-principles simulations of 2DES spectra.[1] The methodology has been so far applied to the study of structure and dynamics of various biological systems, including proteic systems [2], organic fluorescent probes [3] and DNA/RNA nucleobases.[4] Wavefunctions methods have been used to reliably calculate the electronic properties of multichromophoric systems, and compared with time-dependent density functional theory methodologies, using hybrid QM/MM schemes and in conjunction with molecular dynamics techniques to assess environmental and conformational effects that shape the 2D electronic spectra [5].

    Recording:

    Video is available only for registered users.

    References

    1. I. Rivalta, Nenov A., Cerullo G., Mukamel S. and Garavelli M. Int. J. Quantum Chem. 2014, 114, 85-93; Segarra-Marti J., Mukamel, S., Garavelli, M., Nenov, A. and Rivalta I. Top. Curr. Chem. 2018, 376, 24.

    2. Nenov A., Mukamel S., Garavelli M. and Rivalta I. J. Chem. Theory Comput. 2015, 11, 3755-3771.

    3. Nenov A., Giussani A., Fingerhut B. P., Rivalta I., Dumont E., Mukamel S. and Garavelli M. Phys. Chem. Chem. Phys. 2015, 46, 30925-30936.

    4. Segarra-Marti J., Jaiswal V. K., Pepino A. J., Giussani A., Nenov A., Mukamel S., Garavelli M. and Rivalta I. Faraday Discuss. 2018, 207, 233-250.

    5. Borrego Varillas R., Nenov A., Ganzer L., Oriana A., Manzoni C., Rivalta I., Mukamel S., Garavelli M., Cerullo G. Chem. Sci., 2019,10, 9907-9921; Segarra-Marti J., Segatta F., Mackenzie T.A., Nenov, A., Rivalta I., Bearpark M.J., Garavelli M. Faraday Discuss., 2020, 221, 219

  • Spectroscopy in the Gas and Condensed Phase: Bridging Theory and Experiments

    Speaker: Assistant Professor Samer Gozem
    Institute: Georgia State University
    Country: USA
    Speaker Link: http://gozemlab.com/
    Time: 19:00 CET 21-Feb-22

    Professor Samer Gozem

    Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA

    UV-visible and photoelectron spectroscopy are powerful tools for probing the structure of
    matter from the subatomic to the bulk scale. The experimental spectra are generally
    plotted using two properties: energies and absorption strength (the latter typically reported
    as molar attenuation coefficients or cross sections). Energies and transition strengths
    could also be predicted from first principles with quantum chemical methods. In the gas
    phase, experiments and computations can be reconciled when the appropriate quantum
    chemical methods are used. In the condensed phase, however, experimental spectra are
    shifted and broadened by intermolecular interactions that complicate the comparison
    between theory and computations. At the same time, the condensed-phase spectra
    encode potential important information about these intermolecular interactions and how
    they modulate a solute’s electronic structure. The first part of the presentation will cover
    the basics of computational spectroscopy, and discuss how computed energies and
    intensities can be compared with experimental ones. The second part of the presentation
    will bring the computations into the condensed phase with hybrid quantum chemical /
    molecular mechanical (QM/MM) models, which can be used to understand the effect of a
    solvent (or a protein host) on the spectroscopic properties of a solute (or cofactor).

    Recording:

    Video is available only for registered users.

    References:

    1. Gozem, S.; Krylov, A.I. The ezSpectra suite: An easy‐to‐use toolkit for
    spectroscopy modeling. WIREs Comp. Mol. Sci. e1546. 2021.
    2. Tarleton, A.; Garcia-Alvarez, J.; Wynn, A.; Awbrey, C.; Roberts, T.; Gozem, S.
    OS100: A Benchmark Set of 100 Digitized UV-Visible Spectra and Derived
    Experimental Oscillator Strengths. ChemRxiv 2021. This content is a preprint and
    has not been peer-reviewed.
    3. Dratch, B.D.; Orozco-Gonzalez, Y.; Gadda, G.; Gozem, S. The Ionic Atmosphere
    Effect on the Absorption Spectrum of a Flavoprotein: A Reminder to Consider
    Solution Ions. J. Phys. Chem. Lett. 12 (34), 8384–8396. 2021.
    4. Orozco-Gonzalez, Y.; Kabir, M.P.; Gozem, S. Electrostatic Spectral Tuning Maps
    for Biological Chromophores. J. Phys. Chem. B. 148, 4813—4824. 2019.