Article
Chemistry, Physical
Xiangyu Teng, Alena Sheveleva, Floriana Tuna, Keith R. Willison, Liming Ying
Summary: The interaction between alpha-Synuclein and Cu2+ plays a role in brain copper homeostasis, potentially affecting the progression of Parkinson's disease. While the H50Q mutation does not impact Cu2+ binding to WT-alpha Syn, NAc-alpha Syn shows significantly weaker Cu2+ binding affinity. Cu2+ coordination mode to NAc-alpha Syn has been proposed based on EPR spectrum.
Review
Medicine, General & Internal
E. Srinivasan, G. Chandrasekhar, P. Chandrasekar, K. Anbarasu, A. S. Vickram, Rohini Karunakaran, R. Rajasekaran, P. S. Srikumar
Summary: Parkinson's disease is a neurodegenerative disorder characterized by the loss of dopaminergic neurons, with pathogenesis linked to the misfolding and mutations of alpha-synuclein protein. Genetic and other factors lead to the formation of amyloid structures from alpha-synuclein, causing PD.
FRONTIERS IN MEDICINE
(2021)
Article
Chemistry, Multidisciplinary
Rongying Liu, Ran Zhang, Long Li, Zdravko Kochovski, Lintong Yao, Mu-Ping Nieh, Yan Lu, Tongfei Shi, Guosong Chen
Summary: This study reports a controlled fibril polymorphism library generated by designed glycopeptide building blocks and experimental and computational tools. The growth of fibrils, either axially or radially, is determined by a subtle balance of oligosaccharide and oligopeptide components, leading to right- or left-handed twisting structure. The study also provides visible evidence for the association process of double-strand fibrils, and demonstrates significant differences in macroscopic properties of fibril polymorphs on hydrogel formation and cellular migration control.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Biochemistry & Molecular Biology
Fiamma A. Buratti, Claudio Oscar Fernandez, Markus Zweckstetter
Summary: Parkinson's disease can be either sporadic or inherited, with missense mutations causing the inherited form. The V15A mutation of alpha-synuclein weakens its affinity for membranes but does not significantly affect its conformation in solution. This leads to increased concentration of aggregation-prone alpha-synuclein, allowing the V15A variant to form amyloid fibrils. These findings underscore the importance of maintaining a balance between membrane-bound and free aggregation-competent alpha-synuclein in synucleinopathies.
Article
Multidisciplinary Sciences
Pratibha Kumari, Dhiman Ghosh, Agathe Vanas, Yanick Fleischmann, Thomas Wiegand, Gunnar Jeschke, Roland Riek, Cedric Eichmann
Summary: This study investigated the interaction between monomeric alpha-Syn and its fibrillar form using NMR and electron paramagnetic resonance spectroscopy, revealing that intermolecular interactions reduce intramolecular contacts in monomeric alpha-Syn, leading to further unfolding of its intrinsically disordered states and critically contributing to the aggregation kinetics of alpha-Syn during secondary nucleation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Joana Angelica Loureiro, Stephanie Andrade, Lies Goderis, Ruben Gomez-Gutierrez, Claudio Soto, Rodrigo Morales, Maria Carmo Pereira
Summary: Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by the pathological aggregation of alpha-synuclein leading to Lewy bodies formation. Research indicates that the beta-sheet conformation of alpha-synuclein in the presence of the anionic surfactant SDS stimulates its aggregation process.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Jennifer Ramirez, Samantha X. Pancoe, Elizabeth Rhoades, E. James Petersson
Summary: This article investigates the effects of interactions between the small neuronal protein alpha-synuclein and lipids on aggregation. By analyzing a comprehensive collection of experimental data, the general trends of lipid structure influencing aggregation are identified, providing a resource for interpreting the effects of lipids on aggregation and potentially serving as inputs for computational models.
Article
Chemistry, Physical
Anamika Avni, Ashish Joshi, Samrat Mukhopadhyay
Summary: Vibrational Raman spectroscopy coupled with hydrogen/deuterium exchange can discern key structural features responsible for diverse amyloid polymorphs. This noninvasive and label-free method allows for the structural differentiation of distinct amyloid polymorphs, capturing conformational heterogeneity and structural distributions. This research provides insights into the molecular factors governing structural diversity in amyloid polymorphs and could potentially simplify the study of amyloid remodeling by small molecules.
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
(2023)
Review
Biochemistry & Molecular Biology
Abbie T. Rodger, Maryam A. L. Nasser, Wayne G. Carter
Summary: Currently, there are no pharmacological treatments that can completely stop or reverse the progression of Parkinson's Disease (PD). Therefore, there is a need for neuroprotective therapies. This systematic review examines the effectiveness of anti-a-synuclein (a-syn) therapies in preventing PD progression in preclinical models and human clinical trials. The review found that novel preclinical anti-a-syn therapeutics reduced a-syn aggregations and protected against dopaminergic neuronal loss. Completed clinical trials showed significant tolerability and efficacy in reducing a-syn and minimal adverse effects. Overall, this review highlights the potential of anti-a-syn therapies in both preclinical and clinical settings to reduce a-syn accumulation and potentially slow down PD progression.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Neurosciences
Tiago Fleming Outeiro
Summary: In protein aggregation disorders, oligomeric species may be more toxic than fibrillar forms. Definitive data on the nature of toxic species are lacking due to difficulties in detecting and defining protein aggregate species.
MOLECULAR NEUROBIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Anton B. Matiiv, Svetlana E. Moskalenko, Olga S. Sergeeva, Galina A. Zhouravleva, Stanislav A. Bondarev
Summary: The NOS1AP gene encodes a protein that binds to nNOS and is associated with various disorders. It interacts with alpha-synuclein, suggesting its involvement in synucleinopathies and the relationship between Parkinson's disease and schizophrenia. The molecular mechanisms of these disorders may involve aggregation and misfolding of NOS1AP.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Giulia Marafon, Marco Crisma, Anna Masato, Nicoletta Plotegher, Luigi Bubacco, Alessandro Moretto
Summary: Proteins undergo changes in their 3D structure and function through specific molecular interactions, which is crucial for sensing, processing, and transmitting information from the surrounding environment. The study of early aggregation steps of alpha-synuclein associated with Parkinson's disease showed that light-mediated binding with a photoactive foldamer can promote the process by generating supramolecular fibrillar seeds that act as molecular templates for inducing fast beta-sheet transitions in monomers. This proposed method provides a powerful tool for studying protein aggregation in misfolding diseases in a controlled and inducible system.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Biochemistry & Molecular Biology
Edward Chau, Jin Ryoun Kim
Summary: This study investigated the interactions between Aβ42 and αS in different conformations. It was found that αS monomers and oligomers promoted the oligomerization and stabilization of soluble Aβ42, while αS fibrils hindered the aggregation of Aβ42. These interactions may be achieved through direct binding or co-assembly, and different parts of Aβ42 mediated the interactions with αS.
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
(2022)
Article
Cell Biology
Jonathan D. Horvath, Maria Casas, Candice Kutchukian, Sara Creus Sanchez, Melissa R. Pergande, Stephanie M. Cologna, Sergi Simo, Rose E. Dixon, Eamonn J. Dickson
Summary: Elevated levels of a-Syn cause an increase in PM phosphoinositide PI(4,5)P2, leading to a-Syn aggregation and toxic increases in mitochondrial Ca2+ and reactive oxygen species, resulting in neuronal death. The key players in this process are PIP5K1g and ARF6. Selective inhibition of PIP5K1g or knockout of ARF6 rescues the cellular toxicity. These findings suggest that modulation of phosphoinositide metabolism could be a therapeutic target for PD and related neurodegenerative disorders.
Article
Cell Biology
Srishti Chawla, Doryaneh Ahmadpour, Kara L. Schneider, Navinder Kumar, Arthur Fischbach, Mikael Molin, Thomas Nystrom
Summary: Calcineurin senses changes in calcium concentrations and its inactivation triggers chaperone-associated protein aggregates in yeast. Inactivation of calcineurin also worsens α-Synuclein-related cytotoxicity. On the other hand, activation of calcineurin suppresses protein aggregation and cytotoxicity associated with Parkinson's disease-related mutant α-Synuclein in a partly CRZ1-dependent manner, by promoting proper localization of α-synuclein to the plasma membrane.
CELL COMMUNICATION AND SIGNALING
(2023)
Article
Chemistry, Medicinal
Ke Zuo, Riccardo Capelli, Giulia Rossetti, Rachel Nechushtai, Paolo Carloni
Summary: Human NEET proteins containing iron-sulfur clusters have been identified as potential drug targets for mitochondrial dysfunction-related diseases. However, the lack of understanding of ligand binding to the cytoplasmic domain of NEET protein has hindered rational drug design approaches.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Editorial Material
Neurosciences
Tiago Fleming Outeiro, Omar M. El-Agnaf
NEUROBIOLOGY OF DISEASE
(2023)
Article
Nanoscience & Nanotechnology
Molood Behbahanipour, Roger Benoit, Susanna Navarro, Salvador Ventura
Summary: A novel nanoparticle has been developed that can neutralize SARS-CoV-2 virus. The nanoparticle is biocompatible and stable, and shows potential for therapeutic and diagnostic applications.
ACS APPLIED MATERIALS & INTERFACES
(2023)
Article
Chemistry, Medicinal
Bharath Raghavan, Mirko Paulikat, Katya Ahmad, Lara Callea, Andrea Rizzi, Emiliano Ippoliti, Davide Mandelli, Laura Bonati, Marco De Vivo, Paolo Carloni
Summary: Currently, in silico drug design in the initial stages of drug discovery can benefit from first-principle Quantum Mechanics/Molecular Mechanics (QM/MM) molecular dynamics (MD) simulations in explicit solvent, but many applications are limited by the short time scales that this approach can cover. The development of scalable first principle QM/MM MD interfaces that fully exploit current exascale machines is crucial in overcoming this problem and allowing for the study of ligand binding to protein with first principle accuracy. This study showcases the use of the Multiscale Modeling in Computational Chemistry (MiMiC) QM/MM framework, which demonstrates strong scaling and parallel efficiency of >70% up to >80,000 cores, making it a promising candidate for exascale applications.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Medicinal
Bharath Raghavan, Florian K. Schackert, Andrea Levy, Sophia K. Johnson, Emiliano Ippoliti, Davide Mandelli, Jogvan Magnus Haugaard Olsen, Ursula Rothlisberger, Paolo Carloni
Summary: MiMiC is a flexible and scalable multiscale modeling framework that combines quantum mechanics (QM) and molecular mechanics (MM) codes. The paragraph introduces MiMiCPy, a user-friendly tool written in Python 3 that automates the preparation of MiMiC input files. It also highlights the modular structure of MiMiCPy, allowing for easy extensions to new program formats.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Medicinal
Florian Karl Schackert, Johann Biedermann, Saeid Abdolvand, Sonja Minniberger, Chen Song, Andrew J. R. Plested, Paolo Carloni, Han Sun
Summary: This study investigates calcium conduction in calcium-permeable AMPAR using Molecular Dynamics (MD) simulations and multiscale Quantum Mechanics/Molecular Mechanics (QM/MM) simulations. The results explain the distinct calcium permeability in different RNA-edited forms of GluA2 and provide unprecedented insights into Ca(2+) permeation mechanisms in AMPARs.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Review
Biochemistry & Molecular Biology
Luca Marsili, Jennifer Sharma, Tiago Fleming Outeiro, Carlo Colosimo
Summary: Stem cell-based therapies (SCT) have potential in treating neurodegenerative disorders, but clinical trials are just starting and results may take several years. SCTs can provide both symptomatic and disease-modifying effects, and may complement molecular therapies in precision medicine.
Article
Biology
Emile de Bruyn, Anton Emil Dorn, Olav Zimmermann, Giulia Rossetti
Summary: This study introduces a method called Time-Resolved Radial Distribution Function (TRRDF) to characterize the local environment dynamics around Intrinsically Disordered Proteins (IDPs) that are sensitive to changes in chemical environmental conditions. The authors used their open-source Python package SPEADI to analyze the dynamic distribution of ions around IDPs Alpha-Synuclein (AS) and Humanin (HN) from Molecular Dynamics (MD) simulations, revealing the significant role of ion-residue interactions in the structures and behaviors of IDPs.
Article
Chemistry, Multidisciplinary
Susanna Navarro, Marta Diaz-Caballero, Francesca Peccati, Lorena Roldan-Martin, Mariona Sodupe, Salvador Ventura
Summary: Enzymes fold into specific 3D protein structures and exhibit high catalytic efficiency and selectivity. Artificial amyloids have been shown to have catalytic activity and advantages over natural enzymes. A recent study found that short peptides can self-assemble into amyloid fibrils with catalytic activity by coordinating and retaining different divalent metal cations. These findings provide new insights into the design of artificial metalloenzymes and support the role of amyloid-like structures in the origin of life.
Article
Biochemistry & Molecular Biology
Benjamin Philipp Joseph, Verena Weber, Lisa Knuepfer, Alejandro Giorgetti, Mercedes Alfonso-Prieto, Sybille Krauss, Paolo Carloni, Giulia Rossetti
Summary: In this study, novel HuR inhibitors were identified using a combination of chemoinformatic methods, high-throughput virtual screening, and RNA-protein pulldown assays. The 4-(2-(2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene)hydrazineyl)benzoate ligand showed dose-dependent inhibition of HuR binding. This novel chemical scaffold provides a new avenue for the design of pharmaceutical agents targeting HuR.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
News Item
Biochemistry & Molecular Biology
Javier Garcia-Pardo, Salvador Ventura
NATURE CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Aleksandra E. Badaczewska-Dawid, Aleksander Kuriata, Carlos Pintado-Grima, Javier Garcia-Pardo, Michal Burdukiewicz, Valentin Iglesias, Sebastian Kmiecik, Salvador Ventura
Summary: Protein aggregation is associated with aging and different pathologies, and is a challenge in the industrial production of biotherapeutics. Previous research in model organisms has provided insights into the biophysical principles of this process and led to the development of computational tools. A3D-MODB is a comprehensive database that allows for the study of protein aggregation in 12 model species and provides additional information for better understanding protein aggregation.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Chemistry, Multidisciplinary
Jonas Gossen, Rui Pedro Ribeiro, Dirk Bier, Bernd Neumaier, Paolo Carloni, Alejandro Giorgetti, Giulia Rossetti
Summary: This study presents an approach that combines structural data with a random forest agonist/antagonist classifier and a signal-transduction kinetic model to identify novel chemotype ligands. As a test case, the approach is applied to identify novel antagonists of the human adenosine transmembrane receptor type 2A, a target against Parkinson's disease and cancer.
Article
Chemistry, Physical
Ke Zuo, Agata Kranjc, Riccardo Capelli, Giulia Rossetti, Rachel Nechushtai, Paolo Carloni
Summary: This study introduces a new drug design approach that combines metadynamics free energy methods and experimental structural information to identify ligand poses on protein surfaces.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2023)