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Photoswitchable positive allosteric modulators of metabotropic glutamate receptor 4 to improve selectivity

iScience 2024年第6期27卷 110123页

作者： Panarello, Silvia González-Díez, Aleix Berizzi, Alice E. Malhaire, Fanny Borràs-Tudurí, Roser Rovira, Xavier Serra, Carme Prézeau, Laurent Pin, Jean-Philippe Goudet, Cyril Llebaria, Amadeu Gómez-Santacana, Xavier MCS Institute for Advanced Chemistry of Catalonia – CSIC Barcelona Spain PhD Program in Organic Chemistry of the University of Barcelona Barcelona Spain Institut de Génomique Fonctionnelle Université de Montpellier UMR 5203 CNRS and U 1191 INSERM Montpellier France

Metabotropic glutamate receptors (mGlu) regulate multiple functions in the nervous systems and are involved in several neurological disorders. However, selectively targeting individual mGlu subtypes with spatiotemporal precision is still an unmet need. Photopharmacology can address this concern through the utilization of photoswitchable compounds such as optogluram, which is a positive allosteric modulator (PAM) of mGlu₄ that enables the precise control of physiological responses using light but does not have an optimal selectivity profile. Optogluram analogs were developed to obtain photoswitchable PAMs of mGlu₄ receptor with an improved selectivity. Among them, optogluram-2 emerged as a photoswitchable ligand for mGlu₄ receptor with activity as both PAM and allosteric agonists. It presents a higher selectivity and offers improved photoswitching of mGlu₄ activity. These improved properties make optogluram-2 an excellent candidate to study the role of mGlu₄ with a high spatiotemporal precision in systems where mGlu₄ can be co-expressed with other mGlu receptors. © 2024 The Author(s)

关键词： Biochemistry biological sciences molecular biology natural sciences pharmacology

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Enhancing Protein-Ligand Binding Affinity Predictions using Neural Network Potentials

arXiv

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arXiv 2024年

作者： Zariquiey, Francesc Sabanés Galvelis, Raimondas Gallicchio, Emilio Chodera, John D. Markland, Thomas E. De Fabritiis, Gianni C Dr. Aiguader 88 Barcelona08003 Spain Acellera Labs C Dr Trueta 183 Barcelona08005 Spain Department of Chemistry Brooklyn College of the City University of New York PhD Program in Chemistry Graduate Center of the City University of New York PhD Program in Biochemistry Graduate Center of the City University of New York NY11210 United States Computational and Systems Biology Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New YorkNY10065 United States Department of Chemistry Stanford University 337 Campus Drive StanfordCA94305 United States Passeig Lluis Companys 23 Barcelona08010 Spain

This letter gives results on improving protein-ligand binding affinity predictions based on molecular dynamics simulations using machine learning potentials with a hybrid neural network potential and molecular mechanics methodology (NNP/MM). We compute relative binding free energies (RBFE) with the Alchemical Transfer Method (ATM) and validate its performance against established benchmarks and find significant enhancements compared to conventional MM force fields like GAFF2. Copyright © 2024, The Authors. All rights reserved.

关键词： Molecular dynamics

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Overcoming Cytosolic Delivery Barriers of Proteins Using Denatured Protein-Conjugated Mesoporous Silica Nanoparticles

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ACS Applied Materials and Interfaces 2023年第1期15卷 432-451页

作者： Dembélé, Julien Liao, Jou-Hsuan Liu, Tsang-Pai Chen, Yi-Ping Graduate Institute of Biomedical Materials & Tissue Engineering College of Biomedical Engineering Taipei Medical University Taipei11031 Taiwan Laboratory of Toxicology Environment and Health Doctorate School of Health University Joseph Ki-Zerbo Ouaga03 BP 7021 Burkina Faso Department of Chemistry National Taiwan University Taipei10617 Taiwan Department of Surgery Mackay Memorial Hospital Taipei10449 Taiwan Graduate Institute of Nanomedicine and Medical Engineering Taipei Medical University Taipei11031 Taiwan International PhD Program in Biomedical Engineering College of Biomedical Engineering Taipei Medical University Taipei11031 Taiwan

Intracellular delivery of therapeutic proteins has increased advantages over current small-molecule drugs and gene therapies, especially in therapeutic efficacies for a broad spectrum of diseases. Hence, developing the protein therapeutics approach provides a needed alternative. Here, we designed a mesoporous silica nanoparticle (MSN)-mediated protein delivery approach and demonstrated effective intracellular delivery of the denatured superoxide dismutase (SOD) protein, overcoming the delivery challenges and achieving higher enzymatic activity than native SOD-conjugated MSNs. The denatured SOD-conjugated MSN delivery strategy provides benefits of reduced size and steric hindrance, increased protein flexibility without distorting its secondary structure, exposure of the cell-penetrating peptide transactivator of transcription for enhanced efficient delivery, and a change in the corona protein composition, enabling cytosolic delivery. After delivery, SOD displayed a specific activity around threefold higher than in our previous reports. Furthermore, the in vivo biosafety and therapeutic potential for neuron therapy were evaluated, demonstrating the biocompatibility and the effective antioxidant effect in Neuro-2a cells that protected neurite outgrowth from paraquat-induced reactive oxygen species attack. This study offers an opportunity to realize the druggable possibility of cytosolic proteins using MSNs. © 2022 American Chemical Society.

关键词： Peptides

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Structural insights into the molecular mechanism of phytoplasma immunodominant membrane protein

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IUCrJ 2024年第PT 3期11卷 384-394页

作者： Chang Yi Liu Han Pin Cheng Chan Pin Lin Yi Ting Liao Tzu Ping Ko Shin Jen Lin Shih Shun Lin Hao Ching Wang The PhD Program for Translational Medicine College of Medical Science and Technology Taipei Medical University and Academia Sinica Taipei Taiwan. Institute of Biotechnology National Taiwan University Taipei Taiwan. Institute of Biological Chemistry Academia Sinica Taipei Taiwan. International Center for the Scientific Development of Shrimp Aquaculture National Cheng Kung University Tainan Taiwan.

Immunodominant membrane protein (IMP) is a prevalent membrane protein in phytoplasma and has been confirmed to be an F-actin-binding protein. However, the intricate molecular mechanisms that govern the function of IMP require further elucidation. In this study, the X-ray crystallographic structure of IMP was determined and insights into its interaction with plant actin are provided. A comparative analysis with other proteins demonstrates that IMP shares structural homology with talin rod domain-containing protein 1 (TLNRD1), which also functions as an F-actin-binding protein. Subsequent molecular-docking studies of IMP and F-actin reveal that they possess complementary surfaces, suggesting a stable interaction. The low potential energy and high confidence score of the IMP-F-actin binding model indicate stable binding. Additionally, by employing immunoprecipitation and mass spectrometry, it was discovered that IMP serves as an interaction partner for the phytoplasmal effector causing phyllody 1 (PHYL1). It was then shown that both IMP and PHYL1 are highly expressed in the S2 stage of peanut witches' broom phytoplasma-infected Catharanthus roseus. The association between IMP and PHYL1 is substantiated through in vivo immunoprecipitation, an in vitro cross-linking assay and molecular-docking analysis. Collectively, these findings expand the current understanding of IMP interactions and enhance the comprehension of the interaction of IMP with plant F-actin. They also unveil a novel interaction pathway that may influence phytoplasma pathogenicity and host plant responses related to PHYL1. This discovery could pave the way for the development of new strategies to overcome phytoplasma-related plant diseases.

关键词： X-ray crystallography actin-binding proteins immunodominant membrane proteins phytoplasma protein structure α-helix bundles

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The Scalability of Third Generation Photovoltaics: Deposition Techniques and Modularity

The Scalability of Third Generation Photovoltaics: Depositio...

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2023 Sharjah International Conference on Physics of Advanced Materials, SICPAM 2023

作者： Ayoub, Mohamad Alashkar, Adnan Mdallal, Ayman Ibrahim, Taleb Khamis, Mustafa Alami, Abdul Hai Sustainable and Renewable Energy Engineering Department University of Sharjah Sharjah27272 United Arab Emirates PhD Program in Materials Science and Engineering American University of Sharjah Sharjah26666 United Arab Emirates Department of Chemical Engineering American University of Sharjah Sharjah26666 United Arab Emirates Department of Biology Chemistry and Environmental Sciences College of Arts and Sciences American University of Sharjah Sharjah26666 United Arab Emirates Center for Advanced Materials Research Research Institute of Science and Engineering University of Sharjah Sharjah27272 United Arab Emirates

The development of third-generation photovoltaic (TGPV) technologies promises to address some of the limitations of conventional silicon-based solar cells. However, the scalability of these technologies is a critical factor in their practical application. TGPV include Perovskite Solar Cells (PSC), Organic Solar Cells (OSC), and Dye-Sensitized Solar Cell (DSSC). This paper reviews and summarizes the recent trends and research on the deposition techniques and modularity of TGPV. Various deposition techniques such as slot-die coating, thermal evaporation, and spray pyrolysis are discussed, along with their advantages and limitations. Modularity, which allows for the integration of TGPV cells into different structures, is also examined as a critical factor in scalability. The paper concludes that the scalability of TGPV technologies depends on the development of efficient and cost-effective deposition techniques and modularity, which will facilitate the integration of the TGPV cells into various structures and enable the widespread use of these promising technologies. © Published under licence by IOP Publishing Ltd.

关键词： Perovskite solar cells

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Development of label-free triboelectric nanosensors as screening platforms for anti-tumor drugs

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Nano Energy 2024年 125卷

作者： Cheng, Yu-Ying Ganguly, Anindita Cheng, Yi-Yun Ortiz, Christopher Llynard D. Pal, Arnab Shah, Pramod Kaswan, Kuldeep Yang, Lee-Wei Lin, Zong-Hong Department of Biomedical Engineering National Taiwan University Taipei10617 Taiwan Institute of Biomedical Engineering National Tsing Hua University Hsinchu30013 Taiwan Internet of Senses Research Center National Tsing Hua University Hsinchu30013 Taiwan Praexisio Taiwan Inc. New Taipei221425 Taiwan Institute of Bioinformatics and Structural Biology National Tsing Hua University Hsinchu300044 Taiwan Chemical Biology and Molecular Biophysics Program Taiwan International Graduate Program Institute of Biological Chemistry Academia Sinica Taipei115 Taiwan Department of Chemistry National Tsing Hua University Hsinchu300044 Taiwan International Intercollegiate PhD Program National Tsing Hua University Hsinchu300044 Taiwan Department of Power Mechanical Engineering National Tsing Hua University Hsinchu300044 Taiwan Biomedical Artificial Intelligence PhD Program National Tsing Hua University Hsinchu300044 Taiwan Physics Division National Center for Theoretical Sciences Taipei Taiwan

This study introduces a general label-free drug screening platform with potential to support high-throughput drug screening for any protein target. Its innovation lies in quantifying the affinity of molecule-molecule interactions via voltage output variation, which achieves unprecedented selectivity and sensitivity. It combines computational analysis complemented by experimental substantiation with a solid-liquid triboelectric nanosensor. Owing to its high binding affinity, FKBP-rapamycin is used as a model system to demonstrate the platform's sensitivity. Subsequently, the research is extended to study drug interactions with an oncogenic protein ATG4B. The findings unveil the binding of S130 and Tioconazole to ATG4B, a critical cysteine protease involved in autophagy, while revealing that Dexamethasone does not bind ATG4B. This binding exerts a specific inhibitory effect on autophagic flux and triggers cancer cell apoptosis. The results support the previously verified inhibitory effects of these drugs and the effectiveness of a newly developed self-powered drug screening platform, leveraging the principles of solid-liquid contact electrification. This approach adeptly confronts enduring challenges in traditional drug development methods where biochemical assays need to be designed for each individual protein target or only time-consuming and concentration-demanding molecular interaction measurements were made available. © 2024 Elsevier Ltd

关键词： Nanosensors

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Passivation of Perovskite Films Using Ionic Liquids

Passivation of Perovskite Films Using Ionic Liquids

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2022 Advances in Science and Engineering Technology International Conferences, ASET 2022

作者： Alashkar, Adnan Ibrahim, Taleb Khamis, Mustafa Hai Alami, Abdul American University of Sharjah Materials Science and Engineering PhD Program Sharjah United Arab Emirates American University of Sharjah Department of Chemical Engineering Sharjah United Arab Emirates American University of Sharjah Department of Biology Chemistry and Enviromental Sciences Sharjah United Arab Emirates University of Sharjah Department of Sustainable and Renewable Energy Engineering Sharjah United Arab Emirates

ISBN: (纸本)9781665418010

In this paper, the carrier recombination, and dynamics of Perovskite Solar Cells (PSC) are investigated. Ionic Liquids (IL) are presented in the bulk perovskite in an attempt to improve the dynamics of the charge transport layer. Time Resolved Photoluminescence (TRPL) is utilized to study the fast electronic decay of the perovskite samples and the influence of the IL on the stability of the perovskite film. The ILs are added to the perovskite in three ratios (5%, 10%, and 20%). The results showed that the presence of the ILs increases the electron lifetime inside the perovskite layer. In addition, 10% IL/perovskite displayed the highest increase of 72% in the lifetime. Where, for higher ratios, the lifetime started deteriorating. © 2022 IEEE.

关键词： Ionic liquids

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Validation of the Alchemical Transfer Method for the Estimation of Relative Binding Affinities of Molecular Series

arXiv

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arXiv 2023年

作者： Zariquiey, Francesc Sabanés Pérez, Adrià Majewski, Maciej Gallicchio, Emilio De Fabritiis, Gianni C Dr. Aiguader 88 Barcelona08003 Spain Acellera Labs C Dr Trueta 183 Barcelona08005 Spain Department of Chemistry Brooklyn College of the City University of New York PhD Program in Chemistry Graduate Center of the City University of New York PhD Program in Biochemistry Graduate Center of the City University of New York United States Acellera Devonshire House 582 Honeypot Lane Stanmore Middlesex HA7 1JS United Kingdom Passeig Lluis Companys 23 Barcelona08010 Spain

The accurate prediction of protein-ligand binding affinities is crucial for drug discovery. Alchemical free energy calculations have become a popular tool for this purpose. However, the accuracy and reliability of these methods can vary depending on the methodology. In this study, we evaluate the performance of a relative binding free energy protocol based on the alchemical transfer method (ATM), a novel approach based on a coordinate transformation that swaps the positions of two ligands. The results show that ATM matches the performance of more complex free energy perturbation (FEP) methods in terms of Pearson correlation, but with marginally higher mean absolute errors. This study shows that the ATM method is competitive compared to more traditional methods in speed and accuracy and offers the advantage of being applicable with any potential energy function. Copyright © 2023, The Authors. All rights reserved.

关键词： Ligands

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Construction of Triboelectric Series and Chirality Detection of Amino Acids Using Triboelectric Nanogenerator

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Advanced Science 2024年第4期11卷 e2307266页

作者： Pal, Arnab Ganguly, Anindita Wei, Po-Han Barman, Snigdha Roy Chang, Chia-Chih Lin, Zong-Hong International Intercollegiate PhD Program National Tsing Hua University Hsinchu30013 Taiwan Institute of Biomedical Engineering National Tsing Hua University Hsinchu30013 Taiwan Department of Biomedical Engineering National Taiwan University Taipei10617 Taiwan Department of Applied Chemistry National Yang Ming Chiao Tung University 1001 University Road Hsinchu30010 Taiwan

Triboelectrification necessitates a frictional interaction between two materials, and their contact electrification is characteristically based on the polarity variance in the triboelectric series. Utilizing this fundamental advantage of the triboelectric phenomenon, different materials can be identified according to their contact electrification capability. Herein, an in-depth analysis of the amino acids present in the stratum corneum of human skin is performed and these are quantified regarding triboelectric polarization. The principal focus of this study lies in analyzing and identifying the amino acids present in copious amounts in the stratum corneum to explain their positive behavior during the contact electrification process. Thus, an augmented triboelectric series of amino acids with quantified triboelectric charging polarity by scrutinizing the transfer charge, work function, and atomic percentage is presented. Furthermore, the chirality of aspartic acid as it is most susceptible to racemization with clear consequences on the human skin is detected. The study is expected to accelerate research exploiting triboelectrification and provide valuable information on the surface properties and biological activities of these important biomolecules. © 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.

关键词： Amino acids

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Probabilistic genotype-phenotype maps reveal mutational robustness of RNA folding, spin glasses, and quantum circuits

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Physical Review Research 2025年第1期7卷 013118-013118页

作者： Anna Sappington Vaibhav Mohanty Department of Electrical Engineering and Computer Science Massachusetts Institute of Technology Cambridge Massachusetts 02139 USA Harvard-MIT Program in Health Sciences and Technology Harvard Medical School Boston Massachusetts 02115 USA and Massachusetts Institute of Technology Cambridge Massachusetts 02139 USA Harvard/MIT MD-PhD Program Harvard Medical School Boston Massachusetts 02115 USA and Massachusetts Institute of Technology Cambridge Massachusetts 02139 USA Department of Chemistry and Chemical Biology Harvard University Cambridge Massachusetts 02138 USA

Recent studies of genotype-phenotype maps have reported universally enhanced phenotypic robustness to genotype mutations, a feature essential to evolution. Virtually all of these studies make a simplifying assumption that each genotype—represented as a sequence—maps deterministically to a single phenotype, such as a discrete structure. Here we introduce probabilistic genotype-phenotype (PrGP) maps, where each genotype maps to a vector of phenotype probabilities, as a more realistic and universal language for investigating robustness in a variety of physical, biological, and computational systems. We study three model systems to show that PrGP maps offer a generalized framework which can handle uncertainty emerging from various physical sources: (1) thermal fluctuation in RNA folding, (2) external field disorder in the spin-glass ground state search problem, and (3) superposition and entanglement in quantum circuits, which are realized experimentally on IBM quantum computers. In all three cases, we observe a biphasic robustness scaling which is enhanced relative to random expectation for more frequent phenotypes and approaches random expectation for less frequent phenotypes. We derive an analytical theory for the behavior of PrGP robustness, and we demonstrate that the theory is highly predictive of empirical robustness.

关键词： Quantum computers

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