Article
Immunology
Somanath Kallolimath, Roman Palt, Esther Foederl-Hoebenreich, Lin Sun, Qiang Chen, Florian Pruckner, Lukas Eidenberger, Richard Strasser, Kurt Zatloukal, Herta Steinkellner
Summary: This study successfully produced pentameric IgM antibodies in glycoengineered plants that carry a highly reproducible human-type N-glycosylation profile. The pentameric IgMs showed increased antigen binding and virus neutralization potency, up to 390-fold, compared to the parental IgG1.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Multidisciplinary Sciences
Daniel Luque, Theodoros Goulas, Carlos P. Mata, Soraia R. Mendes, F. Xavier Gomis-Ruth, Jose R. Caston
Summary: In this study, the molecular mechanism of the inhibitory function of human alpha(2)-macroglobulin was dissected using cryo-EM structures. The results demonstrate that h alpha M-2 forms an inhibitory trap through conformational transitions, allowing it to regulate circulating proteases.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Chemistry, Multidisciplinary
Perrine M. R. Wingering, Silvia Hohnstein, Felix Kraemer, Melina E. A. Dilanas, Cristina Ruiz-Martinez, Ignacio Fernandez, Frank Breher
Summary: The synthesis and characterization of rare earth element complexes (Ln=Y, La, Sm, Lu, Ce) of several podant & kappa;N-6-coordinating ligands were conducted. The structural properties of the complexes were studied using X-ray diffraction and advanced NMR methods. To evaluate the donor capabilities of the ligands, cyclic voltammetry, absorption experiments, and Y-89 NMR chemical shift analysis were performed. Quantum chemical calculations were also used to support the experimental findings. Furthermore, coordination competition studies were carried out using H-1 and P-31 NMR spectroscopy to investigate the correlation with donor properties and selectivity.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Chemistry, Medicinal
Maximilian Meixner, Martin Zachmann, Sebastian Metzler, Jonathan Scheerer, Martin Zacharias, Iris Antes
Summary: Macrocycles are challenging molecules for computational modeling studies, but the accurate prediction of their bioactive conformations can be achieved through the optimization of sampling and docking processes.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Chemistry, Physical
Tino P. Golub, Christian Merten
Summary: The study demonstrates that VCD spectroscopy can provide insights into the conformational preferences of the iminium ion obtained from MacMillan's imidazolidinone catalyst, confirming the dominance of a specific structure. Visual comparison of experimental and computed VCD spectra allows for the identification of the main conformer without in-depth interpretation of the spectroscopic data. Additionally, VCD spectroscopy is shown to be capable of detecting small conformational changes induced by solute-solvent and solute-anion interactions.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2021)
Article
Chemistry, Inorganic & Nuclear
Anna G. Matveeva, Anna V. Vologzhanina, Margarita P. Pasechnik, Rinat R. Aysin, Sergey V. Matveet, Yan V. Zubavichus, Oleg I. Artyushin, Elena V. Sharova, Ivan A. Godovikov, Valery K. Brel
Summary: This study synthesized and characterized six new complexes with different ligands and metal ions. The structures and properties of these complexes were investigated using various experimental methods and theoretical calculations.
Article
Chemistry, Multidisciplinary
Daniel Crusius, Jason R. Schnell, Flaviu Cipcigan, Philip C. Biggin
Summary: Knowing the solution structures of cyclic peptides is crucial for predicting the pharmacokinetic properties in drug discovery. In this study, we introduced the MacroConf dataset and computational workflows to evaluate the performance of current in silico methods in reproducing experimental cyclic peptide solution structures. Our findings show that enhanced sampling molecular dynamics methods, like Gaussian accelerated MD, performed well in reproducing experimental results. Conventional MD suffered from limited sampling, especially for compounds with proline isomerization. Cheminformatics-based conformer generators generated diverse and plausible structures that matched the sampling observed in MD-based methods, but did not provide thermodynamic insights. The presented computational workflow can be easily extended to include new compounds or different simulation methods, serving as a benchmark to improve cyclic peptide conformer generators.
Article
Biochemistry & Molecular Biology
Haoran Yu, Roberto Icken Hernandez Lopez, David Steadman, Daniel Mendez-Sanchez, Sally Higson, Armando Cazares-Koerner, Tom D. Sheppard, John M. Ward, Helen C. Hailes, Paul A. Dalby
Article
Multidisciplinary Sciences
Henry C. Wilkinson, Paul A. Dalby
SCIENTIFIC REPORTS
(2019)
Article
Multidisciplinary Sciences
Henry C. Wilkinson, Paul A. Dalby
SCIENTIFIC REPORTS
(2020)
Review
Chemistry, Multidisciplinary
Veeren M. Chauhan, Hongyu Zhang, Paul A. Dalby, Jonathan W. Aylott
JOURNAL OF CONTROLLED RELEASE
(2020)
Article
Biochemistry & Molecular Biology
Henry C. Wilkinson, Paul A. Dalby
Summary: This study explores the effects of site-specific saturation mutagenesis within enzyme active sites and the potential benefits of incorporating noncanonical amino acids (ncAA) on improving enzyme activity and stability simultaneously. By fine-tuning residue 385 with different aromatic ring substituents, the researchers were able to significantly enhance specific activity, catalytic performance, and stability of the enzyme, showcasing the advantages of expanding designer libraries to include ncAAs.
Article
Multidisciplinary Sciences
Hongyu Zhang, Paul A. Dalby
SCIENTIFIC REPORTS
(2020)
Article
Multidisciplinary Sciences
Pierre-Yves Colin, Paul A. Dalby
SCIENTIFIC REPORTS
(2020)
Article
Biophysics
Valentina A. Spiteri, James Doutch, Robert P. Rambo, Jayesh Gor, Paul A. Dalby, Stephen J. Perkins
Summary: A comparative structural study of glycosylated and deglycosylated monoclonal human IgG1 revealed perturbations in the Fab-Fc separation after deglycosylation, with a broader conformational spectrum observed in the Fc region of deglycosylated IgG1 compared to glycosylated IgG1. This variability in Fc conformations was found to account for the loss of binding to the Fc gamma receptor in deglycosylated IgG1.
BIOPHYSICAL JOURNAL
(2021)
Article
Biochemical Research Methods
John E. Hales, Samir Aoudjane, Gabriel Aeppli, Paul A. Dalby
Summary: The adoption of process analytical technologies in the biopharmaceutical industry can reduce the cost of therapeutic drugs and facilitate investigation of new bioprocesses. Control of critical process parameters is crucial for ensuring product quality, but developing the necessary sophisticated analytical technologies has proven to be a challenge.
JOURNAL OF CHROMATOGRAPHY A
(2021)
Article
Medicine, Research & Experimental
Victoria E. Wood, Kate Groves, Lok Man Wong, Luyan Kong, Christopher Bird, Meenu Wadhwa, Milena Quaglia, Paul Matejtschuk, Paul A. Dalby
Summary: Protein engineering and formulation for therapeutic proteins present a major challenge in the biopharmaceutical industry due to the need for prolonged shelf-life. Understanding the impact of mutations and formulations on protein structure and dynamics can lead to more predictive approaches for improvement. Studies using intrinsic fluorescence analysis and hydrogen deuterium exchange mass spectrometry have revealed insights into the reorganization and stabilization of specific protein loops, providing valuable information for enhancing protein stability and reducing aggregation rates.
MOLECULAR PHARMACEUTICS
(2022)
Article
Medicine, Research & Experimental
Mark-Adam W. Kellerman, Teresa Almeida, Timothy R. Rudd, Paul Matejtschuk, Paul A. Dalby
Summary: Structure-function relationships in proteins are influenced by the trade-off between stability and bioactivity. This study uses NMR spectroscopy to identify key amino acid residues in granulocyte colony-stimulating factor (G-CSF) that affect global stability and undergo conformational changes. It is found that certain residues are important for both stability and function, suggesting a possible link between the two. These findings provide insights into the crucial role of specific residues in the structure-function trade-off of proteins.
MOLECULAR PHARMACEUTICS
(2022)
Article
Medicine, Research & Experimental
Hongyu Zhang, Paul A. Dalby
Summary: Combined administration of antibody therapeutics is beneficial, but the stability of the antibodies may be affected when combined into a single product.
MOLECULAR PHARMACEUTICS
(2022)
Article
Biochemistry & Molecular Biology
Cheng Zhang, Nuria Codina, Jiazhi Tang, Haoran Yu, Nesrine Chakroun, Frank Kozielski, Paul A. Dalby
Summary: The research findings highlighted the different destabilizing pathways of protein structure under low pH and high temperature stress conditions, revealing the potential for stabilizing mutations in the CL domain and C-L-C(H)1 interface. The analysis also identified key salt bridge losses as a cause of conformational changes under different stresses, with implications for future engineering efforts to enhance stability.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Hongyu Zhang, Yang Yang, Cheng Zhang, Suzanne S. Farid, Paul A. Dalby
Summary: By training a neural network model to predict spectra based on the temperature-dependence of intrinsic fluorescence emission under native conditions, hidden information related to stability was discovered in native fluorescence spectra. This method could potentially enable rapid screening of therapeutic protein variants and formulations based on spectroscopic measurements at non-denaturing temperatures.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2021)
Article
Medicine, Research & Experimental
Victoria E. Wood, Kate Groves, Adam Cryar, Milena Quaglia, Paul Matejtschuk, Paul A. Dalby
MOLECULAR PHARMACEUTICS
(2020)