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1. The need to implement FAIR principles in biomolecular simulations

Author

Amaro, Rommie, Åqvist, Johan, Bahar, Ivet, Battistini, Federica, Bellaiche, Adam, Beltran, Daniel, Biggin, Philip C., Bonomi, Massimiliano, Bowman, Gregory R., Bryce, Richard, Bussi, Giovanni, Carloni, Paolo, Case, David, Cavalli, Andrea, Chang, Chie-En A., Cheatham III, Thomas E., Cheung, Margaret S., Chipot, Cris, Chong, Lillian T., Choudhary, Preeti, Cisneros, Gerardo Andres, Clementi, Cecilia, Collepardo-Guevara, Rosana, Coveney, Peter, Covino, Roberto, Crawford, T. Daniel, Peraro, Matteo Dal, de Groot, Bert, Delemotte, Lucie, De Vivo, Marco, Essex, Jonathan, Fraternali, Franca, Gao, Jiali, Gelpí, Josep Lluís, Gervasio, Francesco Luigi, Gonzalez-Nilo, Fernando Danilo, Grubmüller, Helmut, Guenza, Marina, Guzman, Horacio V., Harris, Sarah, Head-Gordon, Teresa, Hernandez, Rigoberto, Hospital, Adam, Huang, Niu, Huang, Xuhui, Hummer, Gerhard, Iglesias-Fernández, Javier, Jensen, Jan H., Jha, Shantenu, Jiao, Wanting, Jorgensen, William L., Kamerlin, Shina Caroline Lynn, Khalid, Syma, Laughton, Charles, Levitt, Michael, Limongelli, Vittorio, Lindahl, Erik, Lindorff-Larsen, Kresten, Loverde, Sharon, Lundborg, Magnus, Luo, Yun Lyna, Luque, Francisco Javier, Lynch, Charlotte I., MacKerell, Alexander, Magistrato, Alessandra, Marrink, Siewert J., Martin, Hugh, McCammon, J. Andrew, Merz, Kenneth, Moliner, Vicent, Mulholland, Adrian, Murad, Sohail, Naganathan, Athi N., Nangia, Shikha, Noe, Frank, Noy, Agnes, Oláh, Julianna, O'Mara, Megan, Ondrechen, Mary Jo, Onuchic, José N., Onufriev, Alexey, Osuna, Silvia, Panchenko, Anna R., Pantano, Sergio, Parish, Carol, Parrinello, Michele, Perez, Alberto, Perez-Acle, Tomas, Perilla, Juan R., Pettitt, B. Montgomery, Pietropalo, Adriana, Piquemal, Jean-Philip, Poma, Adolfo, Praprotnik, Matej, Ramos, Maria J., Ren, Pengyu, Reuter, Nathalie, Roitberg, Adrian, Rosta, Edina, Rovira, Carme, Roux, Benoit, Röthlisberger, Ursula, Sanbonmatsu, Karissa Y., Schlick, Tamar, Shaytan, Alexey K., Simmerling, Carlos, Smith, Jeremy C., Sugita, Yuji, Świderek, Katarzyna, Taiji, Makoto, Tao, Peng, Tikhonova, Irina G., Tirado-Rives, Julian, Tunón, Inaki, Van Der Kamp, Marc W., Van der Spoel, David, Velankar, Sameer, Voth, Gregory A., Wade, Rebecca, Warshel, Ariel, Welborn, Valerie Vaissier, Wetmore, Stacey, Wong, Chung F., Yang, Lee-Wei, Zacharias, Martin, and Orozco, Modesto

Subjects
Quantitative Biology - Biomolecules
Abstract

This letter illustrates the opinion of the molecular dynamics (MD) community on the need to adopt a new FAIR paradigm for the use of molecular simulations. It highlights the necessity of a collaborative effort to create, establish, and sustain a database that allows findability, accessibility, interoperability, and reusability of molecular dynamics simulation data. Such a development would democratize the field and significantly improve the impact of MD simulations on life science research. This will transform our working paradigm, pushing the field to a new frontier. We invite you to support our initiative at the MDDB community (https://mddbr.eu/community/)

Published
2024

3. Comprehensive characterization of the neurogenic and neuroprotective action of a novel TrkB agonist using mouse and human stem cell models of Alzheimer’s disease

Author

Charou, Despoina, Rogdakis, Thanasis, Latorrata, Alessia, Valcarcel, Maria, Papadogiannis, Vasileios, Athanasiou, Christina, Tsengenes, Alexandros, Papadopoulou, Maria Anna, Lypitkas, Dimitrios, Lavigne, Matthieu D., Katsila, Theodora, Wade, Rebecca C., Cader, M. Zameel, Calogeropoulou, Theodora, Gravanis, Achille, and Charalampopoulos, Ioannis

Published
2024
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7. Myotubularin-related-protein-7 inhibits mutant (G12V) K-RAS by direct interaction

Author

Weidner, Philip, Saar, Daniel, Söhn, Michaela, Schroeder, Torsten, Yu, Yanxiong, Zöllner, Frank G., Ponelies, Norbert, Zhou, Xiaobo, Zwicky, André, Rohrbacher, Florian N., Pattabiraman, Vijaya R., Tanriver, Matthias, Bauer, Alexander, Ahmed, Hazem, Ametamey, Simon M., Riffel, Philipp, Seger, Rony, Bode, Jeffrey W., Wade, Rebecca C., Ebert, Matthias P.A., Kragelund, Birthe B., and Burgermeister, Elke

Published
2024
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8. Destabilizers of the thymidylate synthase homodimer accelerate its proteasomal degradation and inhibit cancer growth

Author

Costantino, Luca, Ferrari, Stefania, Santucci, Matteo, Salo-Ahen, Outi MH, Carosati, Emanuele, Franchini, Silvia, Lauriola, Angela, Pozzi, Cecilia, Trande, Matteo, Gozzi, Gaia, Saxena, Puneet, Cannazza, Giuseppe, Losi, Lorena, Cardinale, Daniela, Venturelli, Alberto, Quotadamo, Antonio, Linciano, Pasquale, Tagliazucchi, Lorenzo, Moschella, Maria Gaetana, Guerrini, Remo, Pacifico, Salvatore, Luciani, Rosaria, Genovese, Filippo, Henrich, Stefan, Alboni, Silvia, Santarem, Nuno, da Silva Cordeiro, Anabela, Giovannetti, Elisa, Peters, Godefridus J, Pinton, Paolo, Rimessi, Alessandro, Cruciani, Gabriele, Stroud, Robert M, Wade, Rebecca C, Mangani, Stefano, Marverti, Gaetano, D'Arca, Domenico, Ponterini, Glauco, and Costi, Maria Paola

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Women's Health, Biotechnology, Orphan Drug, Rare Diseases, Cancer, Digestive Diseases, Ovarian Cancer, 5.1 Pharmaceuticals, Female, Animals, Mice, Humans, Binding Sites, Thymidylate Synthase, Fluorouracil, Ovarian Neoplasms, Enzyme Inhibitors, thymidylate synthase, protein dimer destabilizers, cancer growth inhibition, proteasomal degradation, enzyme dissociative inhibition mechanism, target engagement, Human, biochemistry, cancer biology, chemical biology, human, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Drugs that target human thymidylate synthase (hTS), a dimeric enzyme, are widely used in anticancer therapy. However, treatment with classical substrate-site-directed TS inhibitors induces over-expression of this protein and development of drug resistance. We thus pursued an alternative strategy that led us to the discovery of TS-dimer destabilizers. These compounds bind at the monomer-monomer interface and shift the dimerization equilibrium of both the recombinant and the intracellular protein toward the inactive monomers. A structural, spectroscopic, and kinetic investigation has provided evidence and quantitative information on the effects of the interaction of these small molecules with hTS. Focusing on the best among them, E7, we have shown that it inhibits hTS in cancer cells and accelerates its proteasomal degradation, thus causing a decrease in the enzyme intracellular level. E7 also showed a superior anticancer profile to fluorouracil in a mouse model of human pancreatic and ovarian cancer. Thus, over sixty years after the discovery of the first TS prodrug inhibitor, fluorouracil, E7 breaks the link between TS inhibition and enhanced expression in response, providing a strategy to fight drug-resistant cancers.

Published
2022

9. Three-fold mechanism of inhibition of SARS-CoV-2 infection by the interaction of the spike glycoprotein with heparin

Author

Paiardi, Giulia, Richter, Stefan, Oreste, Pasqua, Urbinati, Chiara, Rusnati, Marco, and Wade, Rebecca C.

Subjects
Quantitative Biology - Biomolecules
Abstract

Heparin has been found to have antiviral activity against SARS-CoV-2. Here, by means of sliding window docking, molecular dynamics simulations and biochemical assays, we investigate the binding mode of heparin to the virus spike glycoprotein and the molecular basis for its antiviral activity. The simulations show that heparin binds at long, mostly positively charged patches on the spike, thereby masking the basic residues of the receptor binding domain and of the S1/S2 site. Experiments corroborated the simulation results by showing that heparin inhibits the cleavage of spike by furin by binding to the basic S1/S2 site. Our results indicate that heparin exerts its antiviral activity by both direct and allosteric mechanisms. Furthermore, the simulations provide insights into how heparan sulfate proteoglycans on the host cell can facilitate viral infection. Our results will aid the rational optimization of heparin derivatives for SARS-CoV-2 antiviral therapy.

Published
2021

10. Brownian Dynamics Simulations of Proteins in the Presence of Surfaces: Long-range Electrostatics and Mean-field Hydrodynamics

Author

Reinhardt, Martin, Bruce, Neil J., Kokh, Daria B., and Wade, Rebecca C.

Subjects
Condensed Matter - Soft Condensed Matter, Physics - Biological Physics
Abstract

Simulations of macromolecular diffusion and adsorption in confined environments can offer valuable mechanistic insights into numerous biophysical processes. In order to model solutes at atomic detail on relevant time scales, Brownian Dynamics simulations can be carried out with the approximation of rigid body solutes moving through a continuum solvent. This allows the precomputation of interaction potential grids for the solutes, thereby allowing the computationally efficient calculation of forces. However, hydrodynamic and long-range electrostatic interactions cannot be fully treated with grid-based approaches alone. Here, we develop a treatment of both hydrodynamic and electrostatic interactions to include the presence of surfaces by modeling grid-based and long-range interactions. We describe its application to simulate the self-association and many-molecule adsorption of the well-characterized protein Hen Egg-White Lysozyme to mica-like and silica-like surfaces. We find that the computational model can recover a number of experimental observables of the adsorption process and provide insights into their determinants. The computational model is implemented in the Simulation of Diffusional Association (SDA) software package.

Published
2020

11. Ligand unbinding mechanisms and kinetics for T4 lysozyme mutants from tauRAMD simulations

Author

Nunes-Alves, Ariane, Kokh, Daria B., and Wade, Rebecca C.

Subjects
Quantitative Biology - Quantitative Methods, Quantitative Biology - Biomolecules
Abstract

The protein-ligand residence time, tau, influences molecular function in biological networks and has been recognized as an important determinant of drug efficacy. To predict tau, computational methods must overcome the problem that tau often exceeds the timescales accessible to conventional molecular dynamics (MD) simulation. Here, we apply the tau-Random Acceleration Molecular Dynamics (tauRAMD) method to a set of kinetically characterized complexes of T4 lysozyme mutants with engineered binding cavities. tauRAMD yields relative ligand dissociation rates in good accordance with experiments and thereby allows a comprehensive characterization of the ligand egress routes and determinants of tau. Although ligand dissociation by multiple egress routes is observed, we find that egress via the predominant route determines the value of tau. We also find that the presence of metastable states along egress pathways slows down protein-ligand dissociation. These physical insights could be exploited in the rational optimization of the kinetic properties of drug candidates., Comment: Changes in the format of the manuscript

Published
2020
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12. A Workflow for Exploring Ligand Dissociation from a Macromolecule: Efficient Random Acceleration Molecular Dynamics Simulation and Interaction Fingerprints Analysis of Ligand Trajectories

Author

Kokha, Daria B., Doser, Bernd, Richter, Stefan, Ormersbach, Fabian, Cheng, Xingyi, and Wade, Rebecca C.

Subjects
Quantitative Biology - Biomolecules, Physics - Biological Physics, Physics - Chemical Physics
Abstract

The dissociation of ligands from proteins and other biomacromolecules occurs over a wide range of timescales. For most pharmaceutically relevant inhibitors, these timescales are far beyond those that are accessible by conventional molecular dynamics (MD) simulation. Consequently, to explore ligand egress mechanisms and compute dissociation rates, it is necessary to enhance the sampling of ligand unbinding. Random Acceleration MD (RAMD) is a simple method to enhance ligand egress from a macromolecular binding site, which enables the exploration of ligand egress routes without prior knowledge of the reaction coordinates. Furthermore, the tauRAMD procedure can be used to compute the relative residence times of ligands. When combined with a machine-learning analysis of protein-ligand interaction fingerprints (IFPs), molecular features that affect ligand unbinding kinetics can be identified. Here, we describe the implementation of RAMD in GROMACS 2020, which provides significantly improved computational performance, with scaling to large molecular systems. For the automated analysis of RAMD results, we developed MD-IFP, a set of tools for the generation of IFPs along unbinding trajectories and for their use in the exploration of ligand dynamics. We demonstrate that the analysis of ligand dissociation trajectories by mapping them onto the IFP space enables the characterization of ligand dissociation routes and metastable states. The combined implementation of RAMD and MD-IFP provides a computationally efficient and freely available workflow that can be applied to hundreds of compounds in a reasonable computational time and will facilitate the use of tauRAMD in drug design., Comment: 35 pages, 5 figures in the main text and 9 figures in the supplementary information. The following article has been submitted to The Journal of Chemical Physics. After it is published, it will be found at https://publishing.aip.org/resources/librarians/products/journals/

Published
2020
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13. Recent progress in molecular simulation methods for drug binding kinetics

Author

Nunes-Alves, Ariane, Kokh, Daria B., and Wade, Rebecca C.

Subjects
Quantitative Biology - Quantitative Methods, Quantitative Biology - Biomolecules
Abstract

Due to the contribution of drug-target binding kinetics to drug efficacy, there is a high level of interest in developing methods to predict drug-target binding kinetic parameters. During the review period, a wide range of enhanced sampling molecular dynamics simulation-based methods has been developed for computing drug-target binding kinetics and studying binding and unbinding mechanisms. Here, we assess the performance of these methods considering two benchmark systems in detail: mutant T4 lysozyme-ligand complexes and a large set of N-HSP90-inhibitor complexes. The results indicate that some of the simulation methods can already be usefully applied in drug discovery or lead optimization programs but that further studies on more high-quality experimental benchmark datasets are necessary to improve and validate computational methods., Comment: Figure 3 was improved. A definition of PIB was included. Reference to WE was added (ref. 20), reference to RAMD was corrected (ref. 43)

Published
2020
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14. Design, synthesis and biological evaluation of antiparasitic dinitroaniline-ether phospholipid hybrids

Author

Roussaki, Marina, Magoulas, George E., Fotopoulou, Theano, Santarem, Nuno, Barrias, Emile, Pöhner, Ina, Luelmo, Sara, Afroudakis, Pantelis, Georgikopoulou, Kalliopi, Nevado, Paloma Tejera, Eick, Julia, Bifeld, Eugenia, Corral, María J., Jiménez-Antón, María Dolores, Ellinger, Bernhard, Kuzikov, Maria, Fragiadaki, Irini, Scoulica, Effie, Gul, Sheraz, Clos, Joachim, Prousis, Kyriakos C., Torrado, Juan J., Alunda, José María, Wade, Rebecca C., de Souza, Wanderley, Cordeiro da Silva, Anabela, and Calogeropoulou, Theodora

Published
2023
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17. Allostery in Its Many Disguises: From Theory to Applications

Author

Wodak, Shoshana J, Paci, Emanuele, Dokholyan, Nikolay V, Berezovsky, Igor N, Horovitz, Amnon, Li, Jing, Hilser, Vincent J, Bahar, Ivet, Karanicolas, John, Stock, Gerhard, Hamm, Peter, Stote, Roland H, Eberhardt, Jerome, Chebaro, Yassmine, Dejaegere, Annick, Cecchini, Marco, Changeux, Jean-Pierre, Bolhuis, Peter G, Vreede, Jocelyne, Faccioli, Pietro, Orioli, Simone, Ravasio, Riccardo, Yan, Le, Brito, Carolina, Wyart, Matthieu, Gkeka, Paraskevi, Rivalta, Ivan, Palermo, Giulia, McCammon, J Andrew, Panecka-Hofman, Joanna, Wade, Rebecca C, Di Pizio, Antonella, Niv, Masha Y, Nussinov, Ruth, Tsai, Chung-Jung, Jang, Hyunbum, Padhorny, Dzmitry, Kozakov, Dima, and McLeish, Tom

Subjects
Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance, Allosteric Regulation, Allosteric Site, Animals, Biosensing Techniques, Drug Design, Gene Expression Regulation, Humans, Metabolic Networks and Pathways, Molecular Dynamics Simulation, Proteins, Signal Transduction, Thermodynamics, Transcription, Genetic, Allostery, allosteric drugs, allosteric material, allosteric switches, elastic network models, energy landscape, molecular dynamics, protein conformational changes, protein function, regulation, signal transduction, Biophysics
Abstract

Allosteric regulation plays an important role in many biological processes, such as signal transduction, transcriptional regulation, and metabolism. Allostery is rooted in the fundamental physical properties of macromolecular systems, but its underlying mechanisms are still poorly understood. A collection of contributions to a recent interdisciplinary CECAM (Center Européen de Calcul Atomique et Moléculaire) workshop is used here to provide an overview of the progress and remaining limitations in the understanding of the mechanistic foundations of allostery gained from computational and experimental analyses of real protein systems and model systems. The main conceptual frameworks instrumental in driving the field are discussed. We illustrate the role of these frameworks in illuminating molecular mechanisms and explaining cellular processes, and describe some of their promising practical applications in engineering molecular sensors and informing drug design efforts.

Published
2019

20. Multiresolution molecular dynamics simulations reveal the interplay between conformational variability and functional interactions in membrane‐bound cytochrome P450 2B4.

Author

Han, Sungho Bosco, Teuffel, Jonathan, Mukherjee, Goutam, and Wade, Rebecca C.

Abstract

Cytochrome P450 2B4 (CYP 2B4) is one of the best‐characterized CYPs and serves as a key model system for understanding the mechanisms of microsomal class II CYPs, which metabolize most known drugs. The highly flexible nature of CYP 2B4 is apparent from crystal structures that show the active site with either a wide open or a closed heme binding cavity. Here, we investigated the conformational ensemble of the full‐length CYP 2B4 in a phospholipid bilayer, using multiresolution molecular dynamics (MD) simulations. Coarse‐grained MD simulations revealed two predominant orientations of CYP 2B4's globular domain with respect to the bilayer. Their refinement by atomistic resolution MD showed adaptation of the enzyme's interaction with the lipid bilayer, leading to open configurations that facilitate ligand access to the heme binding cavity. CAVER analysis of enzyme tunnels, AquaDuct analysis of water routes, and Random Acceleration Molecular Dynamics simulations of ligand dissociation support the conformation‐dependent passage of molecules between the active site and the protein surroundings. Furthermore, simulation of the re‐entry of the inhibitor bifonazole into the open conformation of CYP 2B4 resulted in binding at a transient hydrophobic pocket within the active site cavity that may play a role in substrate binding or allosteric regulation. Together, these results show how the open conformation of CYP 2B4 facilitates the binding of substrates from and release of products to the membrane, whereas the closed conformation prolongs the residence time of substrates or inhibitors and selectively allows the passage of smaller reactants via the solvent and water channels. [ABSTRACT FROM AUTHOR]

Published
2024
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21. Dangers of disposable electronic devices

Author

Young, Laura, primary, Dawson, Sue, additional, Lavallee, David, additional, Midownik, Mark, additional, Napper, Imogen, additional, Thompson, Richard, additional, and Wade, Rebecca, additional

Published
2024
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29. Hotspots in an Obligate Homodimeric Anticancer Target. Structural and Functional Effects of Interfacial Mutations in Human Thymidylate Synthase

Author

Salo-Ahen, Outi H., Tochowicz, Anna, Pozzi, Cecilia, Cardinale, Daniela, Ferrari, Stefania, Boum, Yap, Mangani, Stefano, Stroud, Robert M., Saxena, Puneet, Myllykallio, Hannu, Costi, Maria Paola, Ponterini, Glauco, and Wade, Rebecca C.

Abstract

Human thymidylate synthase (hTS), a target for antiproliferative drugs, is an obligate homodimer. Single-point mutations to alanine at the monomer–monomer interface may enable the identification of specific residues that delineate sites for drugs aimed at perturbing the protein–protein interactions critical for activity. We computationally identified putative hotspot residues at the interface and designed mutants to perturb the intersubunit interaction. Dimer dissociation constants measured by a FRET-based assay range from 60 nM for wild-type hTS up to about 1 mM for single-point mutants and agree with computational predictions of the effects of these mutations. Mutations that are remote from the active site retain full or partial activity, although the substrate KM values were generally higher and the dimer was less stable. The lower dimer stability of the mutants can facilitate access to the dimer interface by small molecules and thereby aid the design of inhibitors that bind at the dimer interface.Graphical abstract

Published
2015

31. Accelerating Drug Discovery Efforts for Trypanosomatidic Infections Using an Integrated Transnational Academic Drug Discovery Platform

Author

Moraes, Carolina B., Witt, Gesa, Kuzikov, Maria, Ellinger, Bernhard, Calogeropoulou, Theodora, Prousis, Kyriakos C., Mangani, Stefano, Di Pisa, Flavio, Landi, Giacomo, Iacono, Lucia Dello, Pozzi, Cecilia, Freitas-Junior, Lucio H., dos Santos Pascoalino, Bruno, Bertolacini, Claudia P., Behrens, Birte, Keminer, Oliver, Leu, Jennifer, Wolf, Markus, Reinshagen, Jeanette, Cordeiro-da-Silva, Anabela, Santarem, Nuno, Venturelli, Alberto, Wrigley, Stephen, Karunakaran, Deepa, Kebede, Bethlehem, Pöhner, Ina, Müller, Wolfgang, Panecka-Hofman, Joanna, Wade, Rebecca C., Fenske, Martina, Clos, Joachim, Alunda, José María, Corral, María Jesús, Uliassi, Elisa, Bolognesi, Maria Laura, Linciano, Pasquale, Quotadamo, Antonio, Ferrari, Stefania, Santucci, Matteo, Borsari, Chiara, Costi, Maria Paola, and Gul, Sheraz

Published
2019
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33. A community effort in SARS‐CoV‐2 drug discovery

Author

Schimunek, Johannes, primary, Seidl, Philipp, additional, Elez, Katarina, additional, Hempel, Tim, additional, Le, Tuan, additional, Noé, Frank, additional, Olsson, Simon, additional, Raich, Lluís, additional, Winter, Robin, additional, Gokcan, Hatice, additional, Gusev, Filipp, additional, Gutkin, Evgeny M., additional, Isayev, Olexandr, additional, Kurnikova, Maria G., additional, Narangoda, Chamali H., additional, Zubatyuk, Roman, additional, Bosko, Ivan P., additional, Furs, Konstantin V., additional, Karpenko, Anna D., additional, Kornoushenko, Yury V., additional, Shuldau, Mikita, additional, Yushkevich, Artsemi, additional, Benabderrahmane, Mohammed, additional, Bousquet-Melou, Patrick, additional, Bureau, Ronan, additional, Charton, Beatrice, additional, Cirou, Bertrand, additional, Gil, Gérard, additional, Allen, William J., additional, Sirimulla, Suman, additional, Watowich, Stanley, additional, Antonopoulos, Nick, additional, Epitropakis, Nikolaos, additional, Krasoulis, Agamemnon, additional, Pitsikalis, Vassilis, additional, Theodorakis, Stavros, additional, Kozlovskii, Igor, additional, Maliutin, Anton, additional, Medvedev, Alexander, additional, Popov, Petr, additional, Zaretckii, Mark, additional, Eghbal-zadeh, Hamid, additional, Halmich, Christina, additional, Hochreiter, Sepp, additional, Mayr, Andreas, additional, Ruch, Peter, additional, Widrich, Michael, additional, Berenger, Francois, additional, Kumar, Ashutosh, additional, Yamanishi, Yoshihiro, additional, Zhang, Kam, additional, Bengio, Emmanuel, additional, Bengio, Yoshua, additional, Jain, Moksh, additional, Korablyov, Maksym, additional, Liu, Cheng-Hao, additional, Gilles, Marcous, additional, Glaab, Enrico, additional, Barnsley, Kelly, additional, Iyengar, Suhasini M., additional, Ondrechen, Mary Jo, additional, Haupt, V. Joachim, additional, Kaiser, Florian, additional, Schroeder, Michael, additional, Pugliese, Luisa, additional, Albani, Simone, additional, Athanasiou, Christina, additional, Beccari, Andrea, additional, Carloni, Paolo, additional, D'Arrigo, Giulia, additional, Gianquinto, Eleonora, additional, Goßen, Jonas, additional, Hanke, Anton, additional, Joseph, Benjamin P., additional, Kokh, Daria B., additional, Kovachka, Sandra, additional, Manelfi, Candida, additional, Mukherjee, Goutam, additional, Muñiz-Chicharro, Abraham, additional, Musiani, Francesco, additional, Nunes-Alves, Ariane, additional, Paiardi, Giulia, additional, Rossetti, Giulia, additional, Sadiq, S. Kashif, additional, Spyrakis, Francesca, additional, Talarico, Carmine, additional, Tsengenes, Alexandros, additional, Wade, Rebecca, additional, Copeland, Conner, additional, Gaiser, Jeremiah, additional, Olson, Daniel R., additional, Roy, Amitava, additional, Venkatraman, Vishwesh, additional, Wheeler, Travis J., additional, Arthanari, Haribabu, additional, Blaschitz, Klara, additional, Cespugli, Marco, additional, Durmaz, Vedat, additional, Fackeldey, Konstantin, additional, Fischer, Patrick D., additional, Gorgulla, Christoph, additional, Gruber, Christian, additional, Gruber, Karl, additional, Hetmann, Michael, additional, Kinney, Jamie E., additional, Das, Krishna M. Padmanabha, additional, Pandita, Shreya, additional, Singh, Amit, additional, Steinkellner, Georg, additional, Tesseyre, Guilhem, additional, Wagner, Gerhard, additional, Wang, Zi-Fu, additional, Yust, Ryan J., additional, Druzhilovskiy, Dmitry S., additional, Filimonov, Dmitry, additional, Pogodin, Pavel V., additional, Poroikov, Vladimir, additional, Rudik, Anastassia V., additional, Stolbov, Leonid A., additional, Veselovsky, Alexander V., additional, De Rosa, Maria, additional, Simone, Giada De, additional, Gulotta, Maria R., additional, Lombino, Jessica, additional, Mekni, Nedra, additional, Perricone, Ugo, additional, Casini, Arturo, additional, Embree, Amanda, additional, Gordon, D. Benjamin, additional, Lei, David, additional, Pratt, Katelin, additional, Voigt, Christopher A., additional, Chen, Kuang-Yu, additional, Jacob, Yves, additional, Krischuns, Tim, additional, Lafaye, Pierre, additional, Zettor, Agnès, additional, Rodríguez, M. Luis, additional, White, Kris M., additional, Fearon, Daren, additional, von Delft, Frank, additional, Walsh, Martin A., additional, Horvath, Dragos, additional, Brooks, Charles L., additional, Falsafi, Babak, additional, Ford, Bryan, additional, García-Sastre, Adolfo, additional, Lee, Sang Yup, additional, Naffakh, Nadia, additional, Varnek, Alexandre, additional, Klambauer, Guenter, additional, and Hermans, Thomas M., additional

Published
2023
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36. Pedagogic objects : the formation, circulation and exhibition of teaching collections for art and design education in Leeds, 1837-1857

Author

Wade, Rebecca Jayne, Westgarth, M., and Harrison Moore, A.

Subjects
707
Abstract

This thesis identifies and critically examines the teaching collection assembled for the Leeds School of Design, established in 1846 under the Leeds Mechanics’ Institution and Literary Society. The nucleus of this collection was a generic set of plaster casts, prints and publications distributed by the Head School of Design at Somerset House in London, founded in 1837. This approved selection of pedagogic objects was augmented with local donations of paintings, prints, decorative arts and photographs. This thesis proposes that these supplementary objects, and the ways in which they were displayed, represented a resistance to standardisation and a renegotiation of the role of art and design education in relation to existing voluntary societies and their associated public exhibitions. Chapter one investigates the contested curriculum of the Schools of Design and the role of the Royal Academy in its construction. The question addressed concerns how the same reproductions of canonical antique statuary came to be deployed as vehicles for the transmission of a mutable set of ideological positions related to the concepts of art and its applications, industry and consumption and the division of labour. The distinction between the training of the artist and the artisan is also considered on a local level through the Leeds Academy of Arts, which was active between 1852 and 1855. Chapter two explores the philosophical, political and economic positions that informed the practice of the Leeds School of Design, beginning with a Foucauldian analysis of the behaviours and beliefs inculcated in the students through the regulation of space, time and work. The culture of autodidacticism and the associated approaches to political economy developed by Edward Baines Junior and Samuel Smiles are articulated as a means of understanding the climate in which state-sponsored education was received in a regional context. These intellectual conditions are further elaborated through the practice of the travelling public lecture. Chapter three considers the temporary exhibitions, conversazioni and soirées associated with art and design education in Leeds, beginning with the first polytechnic public exhibition organised by the Mechanics’ Institution at the Albion Street Music Hall in 1839. The strategic appropriation of architecture associated with commercial and industrial activity for the purpose of display is considered through the work of Henri Lefebvre on the social production of space. The fourth and final chapter considers the itinerancy of the pedagogic object and the emergence of circulating collections composed of applied arts, reproductions in plaster, fictile ivory and electrotype and photographs. The mobilisation of material culture through these didactic collections will be analysed through a variety of critical frameworks, including historical materialism, post-structuralism and social geography, as appropriate to discrete aspects of the archive.

Published
2012

37. Molecular Modeling in Drug Design

Author

Salo-Ahen, Outi and Wade, Rebecca

Abstract

Since the first attempts at structure-based drug design about four decades ago, molecular modelling techniques for drug design have developed enormously, along with the increasing computational power and structural and biological information of active compounds and potential target molecules. Nowadays, molecular modeling can be considered to be an integral component of the modern drug discovery and development toolbox. Nevertheless, there are still many methodological challenges to be overcome in the application of molecular modeling approaches to drug discovery. The eight original research and five review articles collected in this book provide a snapshot of the state-of-the-art of molecular modeling in drug design, illustrating recent advances and critically discussing important challenges. The topics covered include virtual screening and pharmacophore modelling, chemoinformatic applications of artificial intelligence and machine learning, molecular dynamics simulation and enhanced sampling to investigate contributions of molecular flexibility to drug–receptor interactions, the modeling of drug–receptor solvation, hydrogen bonding and polarization, and drug design against protein–protein interfaces and membrane protein receptors.

Published
2019

38. Diffusion and Association Processes in Biological Systems: Theory, Computation and Experiment

Author

Mereghetti, Paolo, Kokh, Daria, McCammon, J Andrew, and Wade, Rebecca C

Abstract

Abstract Macromolecular diffusion plays a fundamental role in biological processes. Here, we give an overview of recent methodological advances and some of the challenges for understanding how molecular diffusional properties influence biological function that were highlighted at a recent workshop, BDBDB2, the second Biological Diffusion and Brownian Dynamics Brainstorm.

Published
2011

42. Comprehensive characterization of the neurogenic and neuroprotective action of a novel TrkB agonist using mouse and human stem cell models of Alzheimer's Disease

Author

Charou, Despoina, primary, Rogdakis, Thanasis, additional, Latorrata, Alessia, additional, Valcarcel, Maria, additional, Papadogiannis, Vasileios, additional, Athanasiou, Christina, additional, Tsengenes, Alexandros, additional, Papadopoulou, Maria Anna, additional, Lypitkas, Dimitrios, additional, Lavigne, Matthieu D., additional, Katsila, Theodora, additional, Wade, Rebecca C., additional, Cader, Zameel M., additional, Calogeropoulou, Theodora, additional, Gravanis, Achille, additional, and Charalampopoulos, Ioannis, additional

Published
2023
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44. Kinetics for Drug Discovery: an industry-driven effort to target drug residence time

Author

Schuetz, Doris A., de Witte, Wilhelmus Egbertus Arnout, Wong, Yin Cheong, Knasmueller, Bernhard, Richter, Lars, Kokh, Daria B., Sadiq, S. Kashif, Bosma, Reggie, Nederpelt, Indira, Heitman, Laura H., Segala, Elena, Amaral, Marta, Guo, Dong, Andres, Dorothee, Georgi, Victoria, Stoddart, Leigh A., Hill, Steve, Cooke, Robert M., De Graaf, Chris, Leurs, Rob, Frech, Matthias, Wade, Rebecca C., de Lange, Elizabeth Cunera Maria, IJzerman, Adriaan P., Müller-Fahrnow, Anke, and Ecker, Gerhard F.

Published
2017
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49. Hits and Lead Discovery in the Identification of New Drugs against the Trypanosomatidic Infections

Author

Calogeropoulou, Theodora, primary, Magoulas, George E., additional, Pöhner, Ina, additional, Panecka-Hofman, Joanna, additional, Linciano, Pasquale, additional, Ferrari, Stefania, additional, Santarem, Nuno, additional, Jiménez-Antón, Ma Dolores, additional, Olías-Molero, Ana Isabel, additional, Alunda, José María, additional, Silva, Anabela Cordeiro da, additional, Wade, Rebecca C., additional, and Costi, Maria Paola, additional

Published
2019
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