Virtual Winter School on Computational Chemistry
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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.Since these topology/aromaticity switches can be induced by different external stimuli,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.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.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.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. Overall, our work demonstrates how the concept of aromaticity and molecular topology can be exploited to create a novel type of efficient switching devices.
Figure 1.A bottom-up quantum chemical approach to design efficient nanoscale devices.
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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  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 . 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].
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. The methodology has been so far applied to the study of structure and dynamics of various biological systems, including proteic systems , organic fluorescent probes  and DNA/RNA nucleobases. 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 .
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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
Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA
UV-visible and photoelectron spectroscopy are powerful tools for probing the structure ofmatter from the subatomic to the bulk scale. The experimental spectra are generallyplotted using two properties: energies and absorption strength (the latter typically reportedas molar attenuation coefficients or cross sections). Energies and transition strengthscould also be predicted from first principles with quantum chemical methods. In the gasphase, experiments and computations can be reconciled when the appropriate quantumchemical methods are used. In the condensed phase, however, experimental spectra areshifted and broadened by intermolecular interactions that complicate the comparisonbetween theory and computations. At the same time, the condensed-phase spectraencode potential important information about these intermolecular interactions and howthey modulate a solute’s electronic structure. The first part of the presentation will coverthe basics of computational spectroscopy, and discuss how computed energies andintensities can be compared with experimental ones. The second part of the presentationwill 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 asolvent (or a protein host) on the spectroscopic properties of a solute (or cofactor).
1. Gozem, S.; Krylov, A.I. The ezSpectra suite: An easy‐to‐use toolkit forspectroscopy 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 DerivedExperimental Oscillator Strengths. ChemRxiv 2021. This content is a preprint andhas not been peer-reviewed.3. Dratch, B.D.; Orozco-Gonzalez, Y.; Gadda, G.; Gozem, S. The Ionic AtmosphereEffect on the Absorption Spectrum of a Flavoprotein: A Reminder to ConsiderSolution Ions. J. Phys. Chem. Lett. 12 (34), 8384–8396. 2021.4. Orozco-Gonzalez, Y.; Kabir, M.P.; Gozem, S. Electrostatic Spectral Tuning Mapsfor Biological Chromophores. J. Phys. Chem. B. 148, 4813—4824. 2019.
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