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35 Publications visible to you, out of a total of 35
Editorial: The Journal of Molecular Recognition: Changing of the guard

Abstract

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Author: Rebecca C. Wade

Date Published: 1st May 2024

Publication Type: Journal

Multiresolution molecular dynamics simulations reveal the interplay between conformational variability and functional interactions in membrane-bound cytochrome 2B4

Abstract (Expand)

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 …n 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 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.

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

Date Published: 18th Apr 2024

Publication Type: Journal

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

Abstract

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

Date Published: 1st Apr 2024

Publication Type: Journal

Investigation of the impact of mutations in Cytochrome P450 reductase on the rate of electron transfer to Cytochrome P450 by molecular dynamics simulations, (Master’s Thesis), Chemistry, Department of Chemistry, Ruprecht-Karls University, Heidelberg

Abstract

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Editor:

Date Published: 18th Mar 2024

Publication Type: Master's Thesis

The role of heparin in spike SARS-CoV-2 infection: From a model for heparan sulfates to a starting structure for antivirals

Abstract

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Authors: Giulia Paiardi, Maria Milanesi, Matheus Ferraz, Liv Zimmermann, Chiara Urbinati, Pasqua Oreste, Francesca Caccuri, Petr Chlanda, Marco Rusnati, Rebecca C. Wade

Date Published: 1st Feb 2024

Publication Type: Journal

A community effort in SARS‐CoV‐2 drug discovery

Abstract (Expand)

Abstract The COVID‐19 pandemic continues to pose a substantial threat to human lives and is likely to do so for years to come. Despite the availability of vaccines, searching for efficient small‐molecule …r efficient small‐molecule drugs that are widely available, including in low‐ and middle‐income countries, is an ongoing challenge. In this work, we report the results of an open science community effort, the “Billion molecules against COVID‐19 challenge”, to identify small‐molecule inhibitors against SARS‐CoV‐2 or relevant human receptors. Participating teams used a wide variety of computational methods to screen a minimum of 1 billion virtual molecules against 6 protein targets. Overall, 31 teams participated, and they suggested a total of 639,024 molecules, which were subsequently ranked to find ‘consensus compounds’. The organizing team coordinated with various contract research organizations (CROs) and collaborating institutions to synthesize and test 878 compounds for biological activity against proteases (Nsp5, Nsp3, TMPRSS2), nucleocapsid N, RdRP (only the Nsp12 domain), and (alpha) spike protein S. Overall, 27 compounds with weak inhibition/binding were experimentally identified by binding‐, cleavage‐, and/or viral suppression assays and are presented here. Open science approaches such as the one presented here contribute to the knowledge base of future drug discovery efforts in finding better SARS‐CoV‐2 treatments.

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

Date Published: 2024

Publication Type: Journal

An engineered variant of MECR reductase reveals indispensability of long-chain acyl-ACPs for mitochondrial respiration

Abstract (Expand)

Abstract Mitochondrial fatty acid synthesis (mtFAS) is essential for respiratory function. MtFAS generates the octanoic acid precursor for lipoic acid synthesis, but the role of longer fatty acid …thesis, but the role of longer fatty acid products has remained unclear. The structurally well-characterized component of mtFAS, human 2E -enoyl-ACP reductase (MECR) rescues respiratory growth and lipoylation defects of a Saccharomyces cerevisiae Δ etr1 strain lacking native mtFAS enoyl reductase. To address the role of longer products of mtFAS, we employed in silico molecular simulations to design a MECR variant with a shortened substrate binding cavity. Our in vitro and in vivo analyses indicate that the MECR G165Q variant allows synthesis of octanoyl groups but not long chain fatty acids, confirming the validity of our computational approach to engineer substrate length specificity. Furthermore, our data imply that restoring lipoylation in mtFAS deficient yeast strains is not sufficient to support respiration and that long chain acyl-ACPs generated by mtFAS are required for mitochondrial function.

Authors: M. Tanvir Rahman, M. Kristian Koski, Joanna Panecka-Hofman, Werner Schmitz, Alexander J. Kastaniotis, Rebecca C. Wade, Rik K. Wierenga, J. Kalervo Hiltunen, Kaija J. Autio

Date Published: 1st Dec 2023

Publication Type: Journal

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