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Understanding molecular mechanisms of biologics drug delivery and stability from NMR spectroscopy

ADVANCED DRUG DELIVERY REVIEWS 2021年 174卷 1-29页

作者： Phyo, Pyae Zhao, Xi Templeton, Allen C. Xu, Wei Cheung, Jason K. Su, Yongchao Merck & Co Inc Pharmaceut Sci Kenilworth NJ 07033 USA

Protein therapeutics carry inherent limitations of membrane impermeability and structural instability, despite their predominant role in the modern pharmaceutical market. Effective formulations are needed to overcome physiological and physicochemical barriers, respectively, for improving bioavailability and stability. Knowledge of membrane affinity, cellular internalization, encapsulation, and release of drug-loaded carrier vehicles uncover the structural basis for designing and optimizing biopharmaceuticals with enhanced delivery efficiency and therapeutic efficacy. Understanding stabilizing and destabilizing interactions between protein drugs and formulation excipients provide fundamental mechanisms for ensuring the stability and quality of biological products. This article reviews the molecular studies of biologics using solution and solid-state NMR spectroscopy on structural attributes pivotal to drug delivery and stability. In-depth investigation of the structure-function relationship of drug delivery systems based on cell-penetrating peptides, lipid nanoparticles and polymeric colloidal, and biophysical and biochemical stability of peptide, protein, monoclonal antibody, and vaccine, as the integrative efforts on drug product design, will be elaborated. (c) 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://***/licenses/by-nc-nd/4.0/).

关键词： Biologics Drug delivery Lipid nanoparticles structure-function relationships Biophysical characterization NMR spectroscopy

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The intramembrane COOH-terminal domain of PRRT2 regulates voltage-dependent Na plus channels

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JOURNAL OF BIOLOGICAL CHEMISTRY 2023年第5期299卷 104632页

作者： Franchi, Francesca Marte, Antonella Corradi, Beatrice Sterlini, Bruno Alberini, Giulio Romei, Alessandra De Fusco, Antonio Vogel, Alexander Maragliano, Luca Baldelli, Pietro Corradi, Anna Valente, Pierluigi Benfenati, Fabio Ist Italiano Tecnol Ctr Synapt Neurosci & Technol Genoa Italy Univ Genoa Dept Expt Med Genoa Italy IRCCS Osped Policlin San Martino Genoa Italy Polytech Univ Marche Dept Life & Environm Sci Ancona Italy

Proline-rich transmembrane protein 2 (PRRT2) is the single causative gene for pleiotropic paroxysmal syndromes, including epilepsy, kinesigenic dyskinesia, episodic ataxia, and migraine. PRRT2 is a neuron-specific type-2 membrane protein with a COOH-terminal intramembrane domain and a long proline-rich NH2-terminal cytoplasmic region. A large array of experimental data indicates that PRRT2 is a neuron stability gene that negatively controls intrinsic excitability by regulating surface membrane localization and biophysical properties of voltage-dependent Na+ channels Nav1.2 and Nav1.6, but not Nav1.1. To further investigate the regulatory role of PRRT2, we studied the structural features of this membrane protein with molecular dynamics simulations, and its structure-function relationships with Nav1.2 channels by biochemical and elec-trophysiological techniques. We found that the intramembrane COOH-terminal region maintains a stable conformation over time, with the first transmembrane domain forming a helix- loop-helix motif within the bilayer. The unstructured NH2- terminal cytoplasmic region bound to the Nav1.2 better than the isolated COOH-terminal intramembrane domain, mimicking full-length PRRT2, while the COOH-terminal intramembrane domain was able to modulate Na+ current and channel biophysical properties, still maintaining the striking specificity for Nav1.2 versus Nav1.1. channels. The results identify PRRT2 as a dual-domain protein in which the NH2-terminal cytoplasmic region acts as a binding antenna for Na+ channels, while the COOH-terminal membrane domain regulates channel exposure on the membrane and its bio-physical properties.

关键词： PRRT2 voltage-dependent sodium channels molecular dynamics structure-function relationships intrinsic excitability

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Toward More Efficient Organic Solar Cells: A Detailed Study of Loss Pathway and Its Impact on Overall Device Performance in Low-Offset Organic Solar Cells

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ADVANCED ENERGY MATERIALS 2023年第26期13卷 2300980-2300980页

作者： Sun, Bowen Tokmoldin, Nurlan Alqahtani, Obaid Patterson, Acacia De Castro, Catherine S. P. Riley, Drew B. Pranav, Manasi Armin, Ardalan Laquai, Frederic Collins, Brian A. Neher, Dieter Shoaee, Safa Univ Potsdam Inst Phys & Astron Optoelect Disordered Semicond Karl Liebknecht Str 24-25 D-14476 Potsdam Germany Univ Potsdam Inst Phys & Astron Soft Matter Phys & Optoelect Karl Liebknecht Str 24-25 D-14476 Potsdam Germany Washington State Univ Dept Phys & Astron 100 Dairy Rd Pullman WA 99164 USA Prince Sattam bin Abdulaziz Univ Dept Phys Alkharj 11942 Saudi Arabia King Abdullah Univ Sci & Technol KAUST KAUST Solar Ctr KSC Phys Sci & Engn Div PSE Thuwal 239556900 Saudi Arabia Swansea Univ Dept Phys Sustainable Adv Mat Ser SAM Singleton Pk Swansea SA2 8PP Wales

Low-offset organic solar cell systems have attracted great interest since nonfullerene acceptors came into the picture. While numerous studies have focused on the charge generation process in these low-offset systems, only a few studies have focused on the details of each loss channel in the charge generation process and their impact on the overall device performance. Here, several nonfullerene acceptors are blended with the same polymer donor to form a series of low-offset organic solar cell systems where significant variation in device performance is observed. Through detailed analyses of loss pathways, it is found that: i) the donor:acceptor interfaces of PM6:Y6 and PM6:TPT10 are close to the optimum energetic condition, ii) energetics at the donor:acceptor interface are the most important factor to the overall device performance, iii) exciton dissociation yield can be field-dependent owing to the sufficiently small energetic offset at the donor:acceptor interface, and iv) the change in substituents in the terminal group of Y-series acceptors in this work mainly affects energetics at the donor:acceptor interface instead of the interface density in the active layer. In general, this work presents a path toward more efficient organic solar cells.

关键词： exciton reformation field-dependent exciton dissociation loss pathways low-offset NFA organic solar cells structure-function relationships

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Temperature Replica Exchange Molecular Dynamics Simulations of Cyclic Peptide Conformation

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AUSTRALIAN JOURNAL OF CHEMISTRY 2021年第9期74卷 684-685页

作者： Corbett, Karen M. Pouton, Colin W. Chalmers, David K. Monash Univ Monash Inst Pharmaceut Sci 381 Royal Parade Parkville Vic 3052 Australia

Background Cyclic peptides (CPs) have applications as pharmaceuticals, agricultural chemicals, and nanomaterials.[1–4] CPs often take specific, interchanging 3D structures (conformations). The activity of CPs depends... 详细信息

Background Cyclic peptides (CPs) have applications as pharmaceuticals, agricultural chemicals, and nanomaterials.^[1–4^] CPs often take specific, interchanging 3D structures (conformations). The activity of CPs depends on their atomic-level structures and conformational dynamics. Characterising these properties is important to a fundamental understanding of CP function but has historically proven difficult. Molecular dynamics simulations (MDS) represent each atom of the system of interest explicitly and propagate each atom with Newtonian dynamics. MDS allow characterisation of 3D structures of molecules like CPs with atomic-level and femtosecond-level detail. However, systems simulated using conventional MDS can become stuck in free energy minima (Fig. 1), meaning that they are challenged in capturing long-timescale (microsecond and above) CP conformational changes. A special kind of MDS, temperature replica exchange MDS (TREMDS),^[5^] have increasingly been used to study CPs. TREMDS have the advantage of maintaining the atomic-level detail of MDS and capturing long-timescale peptide conformational changes. TREMDS involve concurrently running a series of MDS at various temperatures and swapping between them every so often, allowing enhanced conformational sampling at the lower temperature of interest compared with MDS (Fig. 1).^[5] TREMDS are publicly available within several MDS engines, including GROMACS,^[6^] GENESIS,^[7^] CHARMM,^[8^] and NAMD.^[9^] We note that other kinds of replica exchange MDS also exist;for example, see refs [10–12]. Several studies have reported the remarkable accuracy of TREMDS in the structure prediction of CPs. Geng et al. conducted TREMDS of 20 CPs with known crystal structures.^[13^] Depending on the simulation parameters (i.e. ‘force fields’), approximately half to 15 of the CP crystal

关键词： molecular dynamics replica exchange parallel tempering temperature replica exchange molecular dynamics cyclic peptide structure cyclic peptide conformation structure-function relationships enhanced sampling

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functional molecular switches of mammalian G protein-coupled bitter-taste receptors

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CELLULAR AND MOLECULAR LIFE SCIENCES 2021年第23期78卷 7605-7615页

作者： Topin, Jeremie Bouysset, Cedric Pacalon, Jody Kim, Yiseul Rhyu, Mee-Ra Fiorucci, Sebastien Golebiowski, Jerome Univ Cote dAzur Inst Chim Nice UMR7272 CNRS Nice France Korea Food Res Inst 245 Iseo Myeon Wanju Gun 55365 Jeollabuk Do South Korea DGIST Dept Brain & Cognit Sci 333 Techno JungAng Hyeongpoong Myeon 711873 Daegu South Korea

Bitter taste receptors (TAS2Rs) are a poorly understood subgroup of G protein-coupled receptors (GPCRs). The experimental structure of these receptors has yet to be determined, and key-residues controlling their function remain mostly unknown. We designed an integrative approach to improve comparative modeling of TAS2Rs. Using current knowledge on class A GPCRs and existing experimental data in the literature as constraints, we pinpointed conserved motifs to entirely re-align the amino-acid sequences of TAS2Rs. We constructed accurate homology models of human TAS2Rs. As a test case, we examined the accuracy of the TAS2R16 model with site-directed mutagenesis and in vitro functional assays. This combination of in silico and in vitro results clarifies sequence-function relationships and proposes functional molecular switches that encode agonist sensing and downstream signaling mechanisms within mammalian TAS2Rs sequences.

关键词： Bitter taste receptor GPCR structure-function relationships Integrative structural biology

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Crystal structure of glutamate dehydrogenase 2, a positively selected novel human enzyme involved in brain biology and cancer pathophysiology

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JOURNAL OF NEUROCHEMISTRY 2021年第3期157卷 802-815页

作者： Dimovasili, Christina Fadouloglou, Vasiliki E. Kefala, Aikaterini Providaki, Mary Kotsifaki, Dina Kanavouras, Konstantinos Sarrou, Iosifina Plaitakis, Andreas Zaganas, Ioannis Kokkinidis, Michael Univ Crete Med Sch Neurol Lab Iraklion Crete Greece Fdn Res & Technol Hellas Inst Mol Biol & Biotechnol Nikolaou Plastira 100 Iraklion 70013 Crete Greece Fdn Res & Technol Hellas Dept Biol Iraklion Crete Greece Icahn Sch Med Mt Sinai Ctr Mol Biol & Genet Neurodegenerat Dept Psychiat New York NY 10029 USA Icahn Sch Med Mt Sinai Ctr Mol Biol & Genet Neurodegenerat Dept Neurosci New York NY 10029 USA Democritus Univ Thrace Dept Mol Biol & Genet Alexandroupolis Greece G Gennimatas Gen Hosp Dept Neurol Athens Greece DESY Ctr Free Electron Laser Sci Hamburg Germany

Introduction: Mammalian glutamate dehydrogenase (hGDH1 in human cells) interconverts glutamate to alpha-ketoglutarate and ammonia while reducing NAD(P) to NAD(P)H. During primate evolution, humans and great apes have acquired hGDH2, an isoenzyme that underwent rapid evolutionary adaptation concomitantly with brain expansion, thereby acquiring unique catalytic and regulatory properties that permitted its function under conditions inhibitory to its ancestor hGDH1. Although the 3D-structures of GDHs, including hGDH1, have been determined, attempts to determine the hGDH2 structure were until recently unsuccessful. Comparison of the hGDH1/hGDH2 structures would enable a detailed understanding of their evolutionary differences. This work aimed at the determination of the hGDH2 crystal structure and the analysis of its functional implications. Recombinant hGDH2 was produced in the Spodoptera frugiperda ovarian cell line Sf21, using the Baculovirus expression system. Purification was achieved via a two-step chromatography procedure. hGDH2 was crystallized, X-ray diffraction data were collected using synchrotron radiation and the structure was determined by molecular replacement. The hGDH2 structure is reported at a resolution of 2.9 angstrom. The enzyme adopts a novel semi-closed conformation, which is an intermediate between known open and closed GDH1 conformations, differing from both. The structure enabled us to dissect previously reported biochemical findings and to structurally interpret the effects of evolutionary amino acid substitutions, including Arg470His, on ADP affinity. In conclusion, our data provide insights into the structural basis of hGDH2 properties, the functional evolution of hGDH isoenzymes, and open new prospects for drug design, especially for cancer therapeutics.

关键词： crystal structure glutamate dehydrogenase mitochondrial metabolism molecular evolution structure-function relationships

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Multifunctionality of arginine residues in the active sites of non-canonical D-amino acid transaminases

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ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS 2024年 756卷 110011页

作者： Bakunova, Alina K. Matyuta, Ilya O. Minyaev, Mikhail E. Isaikina, Tatiana Y. Boyko, Konstantin M. Popov, Vladimir O. Bezsudnova, Ekaterina Yu. Russian Acad Sci Bach Inst Biochem Res Ctr Biotechnol Leninsky Ave 33Bld 2 Moscow 119071 Russia Russian Acad Sci ND Zelinsky Inst Organ Chem Leninsky Ave 47 Moscow 119334 Russia Lomonosov Moscow State Univ Dept Biol Leninskie Gory 1Bld 12 Moscow 119991 Russia

structure-function relationships are key to understanding enzyme mechanisms, controlling enzyme activities, and designing biocatalysts. Here, we investigate the functions of arginine residues in the active sites of pyridoxal5 '-phosphate (PLP)-dependent non-canonical D-amino acid transaminases, focusing on the analysis of a transaminase from Haliscomenobacter hydrossis. Our results show that the tandem of arginine residues R28* and R90, which form the conserved R-[RK] motif in non-canonical D-amino acid transaminases, not only facilitates effective substrate binding but also regulates the catalytic properties of PLP. Non-covalent interactions between residues R28*, R90, and Y147 strengthen the hydrogen bond between Y147 and PLP, thereby maintaining the reactivity of the cofactor. Next, the R90 residue contributes to the stability of the holoenzyme. Finally, the R90I substitution induces structural changes that lead to substrate promiscuity, as evidenced by the effective binding of substrates with and without the alpha-carboxylate group. This study sheds light on the structural determinants of the activity of non-canonical D-amino acid transaminases. Understanding the structural basis of the active site plasticity in the non-canonical transaminase from H. hydrossis, which is characterized by effective conversion of D-amino acids and alpha-keto acids, may help to tailor it for industrial applications.

关键词： D -amino acid transaminase structure-function relationships Arginine residues

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Understanding the etiopathogenesis of lumbar intervertebral disc herniation: From clinical evidence to basic scientific research

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JOR SPINE 2024年第1期7卷 e1289页

作者： Zhou, Minhao Theologis, Alekos A. O'Connell, Grace D. Univ Calif Berkeley UC Berkeley Dept Mech Engn 5122 Etcheverry Hall1740 Berkeley CA 94720 USA Univ Calif San Francisco Dept Orthopaed Surg San Francisco CA USA

Lumbar intervertebral disc herniation, as a leading cause of low back pain, productivity loss, and disability, is a common musculoskeletal disorder that results in significant socioeconomic burdens. Despite extensive clinical and basic scientific research efforts, herniation etiopathogenesis, particularly its initiation and progression, is not well understood. Understanding herniation etiopathogenesis is essential for developing effective preventive measures and therapeutic interventions. Thus, this review seeks to provide a thorough overview of the advances in herniation-oriented research, with a discussion on ongoing challenges and potential future directions for clinical, translational, and basic scientific investigations to facilitate innovative interdisciplinary research aimed at understanding herniation etiopathogenesis. Specifically, risk factors for herniation are identified and summarized, including familial predisposition, obesity, diabetes mellitus, smoking tobacco, selected cardiovascular diseases, disc degeneration, and occupational risks. Basic scientific experimental and computational research that aims to understand the link between excessive mechanical load, catabolic tissue remodeling due to inflammation or insufficient nutrient supply, and herniation, are also reviewed. Potential future directions to address the current challenges in herniation-oriented research are explored by combining known progressive development in existing research techniques with ongoing technological advances. More research on the relationship between occupational risk factors and herniation, as well as the relationship between degeneration and herniation, is needed to develop preventive measures for working-age individuals. Notably, researchers should explore using or modifying existing degeneration animal models to study herniation etiopathogenesis, as such models may allow for a better understanding of how to prevent mild-to-moderately degenerated discs from herniating.

关键词： biomechanics injury structure-function relationships

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Small airways vs large airways in asthma: time for a new perspective

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JOURNAL OF APPLIED PHYSIOLOGY 2021年第6期131卷 1839-1841页

作者： Donovan, Graham M. Noble, Peter B. Univ Auckland Dept Math Auckland New Zealand Univ Western Australia Sch Human Sci Crawley WA Australia

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Biochemical and biomechanical characterization of the cervical, thoracic, and lumbar facet joint cartilage in the Yucatan minipig

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JOURNAL OF BIOMECHANICS 2022年 142卷 111238-111238页

作者： Nordberg, Rachel C. Kim, Andrew N. Hight, Justin M. Meka, Rithika S. Elder, Benjamin D. Hu, Jerry C. Athanasiou, Kyriacos A. Univ Calif Irvine Dept Biomed Engn 3131 Engn Hall Irvine CA 92617 USA Mayo Clin Sch Med Dept Neurosurg Orthoped & Biomed Engn 200 1st St SW Rochester MN 55905 USA Univ Calif Irvine Samueli Sch Engn Dept Biomed Engn 3418 Engn Hall Irvine CA 92697 USA

Facet joint arthrosis causes pain in approximately 7 % of the U.S. population, but current treatments are palliative. The objective of this study was to elucidate structure-function relationships and aid in the development of future treatments for the facet joint. This study characterized the articular surfaces of cervical, thoracic, and lumbar facet cartilage from skeletally mature (18-24 mo) Yucatan minipigs. The minipig was selected as the animal model because it is recognized by the U.S. Food and Drug Administration (FDA) and the American Society for Testing and Materials (ASTM) as a translationally relevant model for spine-related indications. It was found that the thoracic facets had a similar to 2 times higher aspect ratio than lumbar and cervical facets. Lumbar facets had 6.9-9.6 times higher % depth than the cervical and thoracic facets. Aggregate modulus values ranged from 135 to 262 kPa, much lower than reported aggregate modulus in the human knee (reported to be 530-701 kPa). The tensile Young's modulus values ranged from 6.7 to 20.3 MPa, with the lumbar superior facet being 304 % and 286 % higher than the cervical inferior and thoracic superior facets, respectively. Moreover, 3D reconstructions of entire vertebral segments were generated. The results of this study imply that structure-function relationships in the facet cartilage are different from other joint cartilages because biochemical properties are analogous to other articular cartilage sources whereas mechanical properties are not. By providing functional properties and a 3D database of minipig facet geometries, this work may supply design criteria for future facet tissue engineering efforts.

关键词： Facet joint Zygapophyseal joint Cartilage Biomechanics structure-function relationships Minipig Characterization

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