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On the determinants of electron transfer reorganization energy in a cytochrome P450: cytochrome b5 complex. A combined quantum mechanics and molecular dynamics simulation study

Abstract (Expand)

The electron transfer steps in the catalytic cycle of cytochrome P450 (CYP) enzymes, ubiquitous proteins with key roles in processes such as drug metabolism and steroidogenesis, are often rate-limiting. …rate-limiting. To predict ET rates from atomistic molecular dynamics simulations using Marcus theory, values of the reaction free energy ΔG0 and the reorganization free energy λ are required from either experiments or computations. For the reduction of cytochrome P450 17A1 (CYP17A1) by the secondary redox protein cytochrome b5 (CYb5), a critical step in the regulation of steroidogenesis, experimental measurements of λ are not available. We here describe the computation of λ for this system from a combination of molecular mechanics/molecular dynamics simulations and quantum mechanics computations. Our results show that a quantum mechanical treatment of the redox-active cofactors is necessary, even though the surrounding protein and solvent, which are modeled classically, contribute most to the reorganization energy. The values of λ computed for structural ensembles corresponding to two predicted binding modes of the proteins are 1.23 and 1.16 eV. We find that the λ values computed for the individual soluble globular domains of the two proteins sum to approximately the λ values computed for the membrane-bound CYP17A1-CYb5 complex, indicating that additivity can be invoked in a computationally efficient approach to estimating λ values for such protein–protein complexes.

Authors: J. Teuffel, G. Mukherjee, S. B. Han, M. Elstner, R. C. Wade

Date Published: 21st May 2025

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: 1st Oct 2024

Publication Type: Journal

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

Abstract (Expand)

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 …hich 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.

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

Date Published: 1st Oct 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

Comparative analysis of drug-salt-polymer interactions by experiment and molecular simulation improves biopharmaceutical performance

Abstract (Expand)

Abstract The propensity of poorly water-soluble drugs to aggregate at supersaturation impedes their bioavailability. Supersaturated amorphous drug-salt-polymer systems provide an emergent approach to …r systems provide an emergent approach to this problem. However, the effects of polymers on drug-drug interactions in aqueous phase are largely unexplored and it is unclear how to choose an optimal salt-polymer combination for a particular drug. Here, we describe a comparative experimental and computational characterization of amorphous solid dispersions containing the drug celecoxib, and a polymer, polyvinylpyrrolidone vinyl acetate (PVP-VA) or hydroxypropyl methylcellulose acetate succinate, with or without Na + /K + salts. Classical models for drug-polymer interactions fail to identify the best drug-salt-polymer combination. In contrast, more stable drug-polymer interaction energies computed from molecular dynamics simulations correlate with prolonged stability of supersaturated amorphous drug-salt-polymer systems, along with better dissolution and pharmacokinetic profiles. The celecoxib-salt-PVP-VA formulations exhibit excellent biopharmaceutical performance, offering the prospect of a low-dosage regimen for this widely used anti-inflammatory, thereby increasing cost-effectiveness, and reducing side-effects.

Authors: Sumit Mukesh, Goutam Mukherjee, Ridhima Singh, Nathan Steenbuck, Carolina Demidova, Prachi Joshi, Abhay T. Sangamwar, Rebecca C. Wade

Date Published: 1st Dec 2023

Publication Type: Journal

Horizons: nuclear astrophysics in the 2020s and beyond

Abstract (Expand)

Abstract Nuclear astrophysics is a field at the intersection of nuclear physics and astrophysics, which seeks to understand the nuclear engines of astronomical objects and the origin of the chemical …the origin of the chemical elements. This white paper summarizes progress and status of the field, the new open questions that have emerged, and the tremendous scientific opportunities that have opened up with major advances in capabilities across an ever growing number of disciplines and subfields that need to be integrated. We take a holistic view of the field discussing the unique challenges and opportunities in nuclear astrophysics in regards to science, diversity, education, and the interdisciplinarity and breadth of the field. Clearly nuclear astrophysics is a dynamic field with a bright future that is entering a new era of discovery opportunities.

Authors: H Schatz, A D Becerril Reyes, A Best, E F Brown, K Chatziioannou, K A Chipps, C M Deibel, R Ezzeddine, D K Galloway, C J Hansen, F Herwig, A P Ji, M Lugaro, Z Meisel, D Norman, J S Read, L F Roberts, A Spyrou, I Tews, F X Timmes, C Travaglio, N Vassh, C Abia, P Adsley, S Agarwal, M Aliotta, W Aoki, A Arcones, A Aryan, A Bandyopadhyay, A Banu, D W Bardayan, J Barnes, A Bauswein, T C Beers, J Bishop, T Boztepe, B Côté, M E Caplan, A E Champagne, J A Clark, M Couder, A Couture, S E de Mink, S Debnath, R J deBoer, J den Hartogh, P Denissenkov, V Dexheimer, I Dillmann, J E Escher, M A Famiano, R Farmer, R Fisher, C Fröhlich, A Frebel, C Fryer, G Fuller, A K Ganguly, S Ghosh, B K Gibson, T Gorda, K N Gourgouliatos, V Graber, M Gupta, W C Haxton, A Heger, W R Hix, W C G Ho, E M Holmbeck, A A Hood, S Huth, G Imbriani, R G Izzard, R Jain, H Jayatissa, Z Johnston, T Kajino, A Kankainen, G G Kiss, A Kwiatkowski, M La Cognata, A M Laird, L Lamia, P Landry, E Laplace, K D Launey, D Leahy, G Leckenby, A Lennarz, B Longfellow, A E Lovell, W G Lynch, S M Lyons, K Maeda, E Masha, C Matei, J Merc, B Messer, F Montes, A Mukherjee, M R Mumpower, D Neto, B Nevins, W G Newton, L Q Nguyen, K Nishikawa, N Nishimura, F M Nunes, E O’Connor, B W O’Shea, W-J Ong, S D Pain, M A Pajkos, M Pignatari, R G Pizzone, V M Placco, T Plewa, B Pritychenko, A Psaltis, D Puentes, Y-Z Qian, D Radice, D Rapagnani, B M Rebeiro, R Reifarth, A L Richard, N Rijal, I U Roederer, J S Rojo, J S K, Y Saito, A Schwenk, M L Sergi, R S Sidhu, A Simon, T Sivarani, Á Skúladóttir, M S Smith, A Spiridon, T M Sprouse, S Starrfield, A W Steiner, F Strieder, I Sultana, R Surman, T Szücs, A Tawfik, F Thielemann, L Trache, R Trappitsch, M B Tsang, A Tumino, S Upadhyayula, J O Valle Martínez, M Van der Swaelmen, C Viscasillas Vázquez, A Watts, B Wehmeyer, M Wiescher, C Wrede, J Yoon, R G T Zegers, M A Zermane, M Zingale

Date Published: 15th Nov 2022

Publication Type: Journal

An electron transfer competent structural ensemble of membrane-bound cytochrome P450 1A1 and cytochrome P450 oxidoreductase

Abstract (Expand)

Abstract Cytochrome P450 (CYP) heme monooxygenases require two electrons for their catalytic cycle. For mammalian microsomal CYPs, key enzymes for xenobiotic metabolism and steroidogenesis and important …roidogenesis and important drug targets and biocatalysts, the electrons are transferred by NADPH-cytochrome P450 oxidoreductase (CPR). No structure of a mammalian CYP–CPR complex has been solved experimentally, hindering understanding of the determinants of electron transfer (ET), which is often rate-limiting for CYP reactions. Here, we investigated the interactions between membrane-bound CYP 1A1, an antitumor drug target, and CPR by a multiresolution computational approach. We find that upon binding to CPR, the CYP 1A1 catalytic domain becomes less embedded in the membrane and reorients, indicating that CPR may affect ligand passage to the CYP active site. Despite the constraints imposed by membrane binding, we identify several arrangements of CPR around CYP 1A1 that are compatible with ET. In the complexes, the interactions of the CPR FMN domain with the proximal side of CYP 1A1 are supplemented by more transient interactions of the CPR NADP domain with the distal side of CYP 1A1. Computed ET rates and pathways agree well with available experimental data and suggest why the CYP–CPR ET rates are low compared to those of soluble bacterial CYPs.

Authors: Goutam Mukherjee, Prajwal P. Nandekar, Rebecca C. Wade

Date Published: 1st Dec 2021

Publication Type: Journal

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