Article
Chemistry, Physical
F. Peter Guengerich, Stella A. Child, Ian R. Barckhausen, Margo H. Goldfarb
Summary: The bacterial cytochrome P450(cam) binds its substrate camphor through an induced-fit mechanism, where the enzyme changes conformation after binding the substrate. This behavior is different from other P450 enzymes that utilize a conformational selection process for substrate recognition. The accessory protein putidaredoxin has no effect on substrate binding, indicating a unique mechanism for substrate recognition by P450(cam).
Article
Engineering, Electrical & Electronic
David C. Ferrier, Janice Kiely, Richard Luxton
Summary: This study presents an enzyme-based electrochemical biosensor for detecting propofol concentrations in total intravenous anesthesia. The sensor demonstrates high sensitivity and good specificity, making it a promising tool for real-time monitoring during the maintenance phase of anesthesia.
IEEE SENSORS JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Manuel Sellner, Andre Fischer, Charleen G. Don, Martin Smiesko
Summary: Research using molecular dynamics simulations and protein-protein docking revealed the mechanism of conformational changes between cytochrome P450 enzymes and cytochrome P450 reductase, as well as proposed new conformational transition mechanisms and structural mechanisms for susceptibility to redox states.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Michelle Redhair, William M. Atkins
Summary: The article discusses the importance of ligand-dependent changes in protein conformation in biology, introducing the induced fit and conformational selection mechanisms, and explaining their impact on protein substrate specificity, promiscuity, and regulatory properties. It also presents a new perspective based on interactions between protein ensembles and ligand ensembles, and describes how probing protein ensembles with multiple ligands can optimize mechanistic information.
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
(2021)
Article
Biochemistry & Molecular Biology
Juan Huang, Qin Xu, Zhuo Liu, Nitin Jain, Madhusudan Tyagi, Dong-Qing Wei, Liang Hong
Summary: This study found that the high density of salt bridges in CYP450 proteins reduces structural flexibility, affecting substrate selection and catalytic activity. By making slight chemical changes, the CYP450 superfamily can regulate the structural flexibility of its member proteins to differentiate substrate specificities.
Review
Chemistry, Multidisciplinary
Iori Morita, Takahiro Mori, Ikuro Abe
Summary: Teleocidins are potent protein kinase C activators with a unique indole-fused nine-membered lactam structure synthesized through a multi-step biosynthetic process involving NRPS, cytochrome P450 oxidase, prenyltransferase, and C-methyltransferase. Recent research has focused on elucidating the molecular basis for the challenging P450-catalyzed intramolecular C-N bond formation, leading to the generation of indolactam scaffold, as well as the production of unnatural and novel molecular scaffolds through precursor-directed biosynthesis using promiscuous P450 enzymes.
CHEMISTRY-A EUROPEAN JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Andre Fischer, Martin Smiesko
Summary: This study investigates an allosteric site in Cytochrome P450 enzymes, finding it to be well conserved in the CYP2 family with the exception of CYP2E1, and observing an enlargement of ligand tunnels in certain members that facilitate ligand translocation. The research contributes to understanding ligand access phenomena and aids in estimating the selectivity of metabolic transformations using computational techniques.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Linda Celeste Montemiglio, Elena Gugole, Ida Freda, Cecile Exertier, Lucia D'Auria, Cheng Giuseppe Chen, Alessandro Nicola Nardi, Gabriele Cerutti, Giacomo Parisi, Marco D'Abramo, Carmelinda Savino, Beatrice Vallone
Summary: This study analyzed the role of a cavity in substrate binding to OleP by mutating its volume. The results showed that inserting bulky residues into the cavity affected the binding properties of the enzyme and perturbed the conformational space of the substrate-enzyme complex. The study highlights the importance of this region in OleP substrate binding and suggests the potential to redirect its activity through this region.
Article
Biotechnology & Applied Microbiology
Shuaiqi Meng, Ruipeng An, Zhongyu Li, Ulrich Schwaneberg, Yu Ji, Mehdi D. Davari, Fang Wang, Meng Wang, Meng Qin, Kaili Nie, Luo Liu
Summary: The study demonstrates how tunnel engineering can modulate substrate preference and improve decarboxylation activity of enzymes, resulting in significantly increased conversion rates for specific fatty acids.
BIORESOURCES AND BIOPROCESSING
(2021)
Article
Biology
Bixia Zhang, ChulHee Kang, Dmitri R. Davydov
Summary: This study investigates the conformational transitions of SbCPR using rapid scanning stop-flow and pressure-perturbation spectroscopy. The results reveal that, although the closed conformation predominates, the population of the open state significantly increases upon the formation of the disemiquinone state. This research not only elucidates the functional choreography of plant CPRs but also demonstrates the high exploratory potential of a combination of pressure-perturbation approach with FRET-based monitoring of protein conformational transitions.
Review
Engineering, Chemical
Outi M. H. Salo-Ahen, Ida Alanko, Rajendra Bhadane, Alexandre M. J. J. Bonvin, Rodrigo Vargas Honorato, Shakhawath Hossain, Andre H. Juffer, Aleksei Kabedev, Maija Lahtela-Kakkonen, Anders Stottrup Larsen, Eveline Lescrinier, Parthiban Marimuthu, Muhammad Usman Mirza, Ghulam Mustafa, Ariane Nunes-Alves, Tatu Pantsar, Atefeh Saadabadi, Kalaimathy Singaravelu, Michiel Vanmeert
Summary: This review provides a comprehensive overview of the current applications of MD in the drug development process, covering target validation, lead discovery, lead optimization, and pharmaceutical formulation development. The importance of MD in providing insights into drug targets, evaluating ligand-receptor interactions, and considering lipid bilayer environments in membrane protein simulations is highlighted. Additionally, the emerging role of MD in studying crystalline and amorphous solids, drug-polymer formulations, drug solubility, and nano-particle simulations is discussed.
Review
Biotechnology & Applied Microbiology
Ondrej Vavra, Jiri Damborsky, David Bednar
Summary: Acceleration of chemical reactions by protein-engineered enzymes is an important contribution of biotechnology to sustainability. Enzymes facilitate the exchange of ligands, ions, and water molecules between the active site and the external environment through tunnels and channels. Molecular docking and molecular dynamics are commonly used methods to study protein-ligand interactions and conformational changes. However, approximative methods have been developed to rapidly simulate binding/unbinding events and provide energy profiles for ligand ranking. This article critically compares these methods, showcases their results, discusses their applications in molecular biotechnology, and explores future developments.
BIOTECHNOLOGY ADVANCES
(2022)
Article
Chemistry, Multidisciplinary
Drew P. Harding, Laura J. Kingsley, Glen Spraggon, Steven E. Wheeler
JOURNAL OF COMPUTATIONAL CHEMISTRY
(2020)
Article
Biochemistry & Molecular Biology
Andre Fischer, Manuel Sellner, Santhosh Neranjan, Martin Smiesko, Markus A. Lill
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2020)
Article
Chemistry, Medicinal
Andre Fischer, Gabriela Frehner, Markus A. Lill, Martin Smiesko
Summary: Thyroid hormone receptors (TRs) are crucial for human development, growth, and metabolism, and antagonists of TRs can effectively treat hyperthyroidism. Computational methods such as MD simulations provide valuable insights into ligand-induced conformational changes in nuclear receptors, which can be important for the development of novel therapeutics.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Biochemistry & Molecular Biology
Andre Fischer, Manuel Sellner, Karolina Mitusinska, Maria Bzowka, Markus A. Lill, Artur Gora, Martin Smiesko
Summary: Research assessed the selectivity of 33 reported non-covalent inhibitors of SARS-CoV-2 M-pro against eight proteases and 16 anti-targets, revealing off-target binding of some compounds to multiple proteases and anti-targets, with a high risk especially in chymase and cathepsin G.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Medicinal
Andre Fischer, Florian Hauptli, Markus A. Lill, Martin Smiesko
Summary: The study found that BF-3 inhibitors are more suitable for combination with classical antiandrogens than AF-2 inhibitors. Classic antiandrogens can cause changes in helix-12 through structural adaptation, accompanied by an expansion of the orthosteric binding site.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Chemistry, Medicinal
Andre Fischer, Martin Smiesko, Manuel Sellner, Markus A. Lill
Summary: This study reviewed the medicinal chemistry literature to explore the importance of visual inspection in molecular docking for drug discovery. Through surveys and expert opinions, valuable insights into visually supported decision-making processes were provided.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Laura J. Kingsley, Xiaohui He, Matthew McNeill, John Nelson, Victor Nikulin, Zhiwei Ma, Wenshuo Lu, Vicki W. Zhou, Mari Manuia, Andreas Kreusch, Mu-Yun Gao, Darbi Witmer, Mei-Ting Vaillancourt, Min Lu, Sarah Greenblatt, Christian Lee, Ajay Vashisht, Steven Bender, Glen Spraggon, Pierre-Yves Michellys, Yong Jia, Jacob R. Haling, Gerald Lelais
Summary: LONP1 is an AAA+ protease essential for maintaining mitochondrial homeostasis, with its inhibitors potentially promoting cancer cell proliferation. This study describes the development of selective boronic acid-based LONP1 inhibitors and the structures of human LONP1 in complex with various inhibitors, providing valuable tools for investigating LONP1 biology.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Andre Fischer, Ferhat Bardakci, Manuel Sellner, Markus A. Lill, Martin Smiesko
Summary: ERR alpha, ERR beta, and ERR gamma are nuclear receptors that regulate metabolic processes in various tissues. They have been implicated as drug targets for important indications. This study used molecular dynamics and metadynamics simulations to investigate the ligand pathways of these receptors, revealing their distribution and their role in ligand translocation.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Multidisciplinary Sciences
Katarzyna Papaj, Patrycja Spychalska, Patryk Kapica, Andre Fischer, Jakub Nowak, Maria Bzowka, Manuel Sellner, Markus A. Lill, Martin Smiesko, Artur Gora
Summary: Based on in silico screening, factor Xa inhibitors were suggested to potentially inhibit SARS-CoV-2 M-pro. However, our study found that the binding affinity of Apixaban, Betrixaban, and Rivaroxaban to SARS-CoV-2 M-pro was weak, indicating a negligible therapeutic effect.
Article
Chemistry, Medicinal
Katarzyna Papaj, Patrycja Spychalska, Katarzyna Hopko, Patryk Kapica, Andre Fisher, Markus A. Lill, Weronika Bagrowska, Jakub Nowak, Katarzyna Szleper, Martin Smiesko, Anna Kasprzycka, Artur Gora
Summary: In this study, a small library of thionocarbamates, thiolocarbamates, sulfide, and disulfide were tested as potential lead compounds for SARS-CoV-2 Mpro drug design using the microscale thermophoresis technique. The identified binder from the thionocarbamates group showed high potential for future modifications to improve affinity and solubility. Computational studies highlighted the inadequacy of simple approaches and the necessity of more advanced methods to properly evaluate the affinity of potential SARS-CoV-2 Mpro binders.
Article
Chemistry, Medicinal
Amr H. Mahmoud, Matthew Masters, Soo Jung Lee, Markus A. Lill
Summary: This research developed a hierarchical approach that can accurately generate samples of large molecular systems from a high-dimensional multimodal equilibrium distribution function using expressive normalizing flows and coarse-grained representation. System specific priors and adaptive and property-based controlled learning were used to reduce the likelihood of generating high-energy structures during sampling. Furthermore, backmapping from a coarse-grained to fully atomistic representation was performed through an equivariant transformer model.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Chemistry, Medicinal
Matthew R. Masters, Amr H. Mahmoud, Yao Wei, Markus A. Lill
Summary: Protein-ligand docking is important in structure-based drug design, but current docking programs lack consideration of protein flexibility. We propose a deep learning model that predicts intermolecular Euclidean distance matrix (EDM) for flexible protein-ligand docking, eliminating the need for iterative search algorithms. The model outperforms other docking methods and generates high quality poses for diverse protein and ligand structures.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Multidisciplinary
Manuel S. Sellner, Amr H. Mahmoud, Markus A. Lill
Summary: In this study, a transformer model was trained to autoencode tokenized SMILES strings using a custom loss function that preserves similarities in latent space. By reducing the similarity between molecules to their Euclidian distance in latent space, the model can perform independent of the similarity metric it was trained on. The method was tested using 2D similarity and showed promise for high-content screening with time-consuming 3D similarity metrics.
JOURNAL OF CHEMINFORMATICS
(2023)
Article
Chemistry, Medicinal
Matthew R. Masters, Amr H. Mahmoud, Yao Wei, Markus A. Lill
Summary: Protein-ligand docking is crucial in drug design, but current docking programs often neglect protein flexibility. To overcome this challenge, we propose a deep learning model based on the prediction of intermolecular Euclidean distance matrix (EDM), eliminating the need for iterative search algorithms. The model, trained on a large-scale dataset, outperforms comparable methods, generating high quality poses for diverse protein-ligand structures.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Meeting Abstract
Biochemistry & Molecular Biology
M. Bzowka, K. Mitusinska, A. Raczynska, A. Samol, A. Fischer, M. Sellner, K. Papaj, P. Spychalska, P. Kapica, K. Hopko, W. Bagrowska, K. Szleper, A. Kasprzycka, J. A. Tuszynski, M. A. Lill, M. Smiesko, A. Gora
Article
Chemistry, Multidisciplinary
Michal Novotny, Matus Dubecky, Frantisek Karlicky
Summary: This paper investigates the accuracy of different DFT-based computational approaches in calculating the equilibrium lattice constants and exfoliation energy of hexagonal boron nitride (h-BN). The results are compared with experiments and reference QMC calculations to evaluate the accuracy of these computational methods.
JOURNAL OF COMPUTATIONAL CHEMISTRY
(2024)
Article
Chemistry, Multidisciplinary
Luigi Crisci, Federico Coppola, Alessio Petrone, Nadia Rega
Summary: The charge transfer dynamics in asymmetrically substituted indenotetracene molecules upon photo-excitation were investigated using real-time time-dependent density functional theory simulations. The study found that the electron-donating character of the substituents affects the overall electronic energy spacing and ultrafast charge transfer dynamics.
JOURNAL OF COMPUTATIONAL CHEMISTRY
(2024)
Article
Chemistry, Multidisciplinary
Vasilii Korotenko, Hendrik Zipse
Summary: The stability of various radicals and molecules has been studied using different theoretical methods, and good correlations between theoretical calculations and experimental results have been found. The effects of hydrogen bonding interactions on the stability of oxygen-centered radicals have also been investigated.
JOURNAL OF COMPUTATIONAL CHEMISTRY
(2024)
Article
Chemistry, Multidisciplinary
Oleg Egorov, Michael Rey, Dominika Viglaska, Andrei V. Nikitin
Summary: In this work, the rovibrational energy levels of four isotopologues of methylene were calculated using a new accurate ab initio potential energy surface. The accuracy of the calculations was improved by considering scalar relativistic effects, DBOC, and high-order electronic correlations. For the first time, all available experimental rovibrational transitions were reproduced with high accuracy, without any empirical corrections.
JOURNAL OF COMPUTATIONAL CHEMISTRY
(2024)