Article
Biochemistry & Molecular Biology
Paola Turina, Piero Fariselli, Emidio Capriotti
Summary: The study of protein folding is crucial for understanding protein function and the relationship between genetics and phenotypes. K-Pro is a new database that collects experimental kinetic data on monomeric proteins with a two-state folding mechanism. It provides a user-friendly interface for browsing and downloading relevant data.
JOURNAL OF MOLECULAR BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Na Le Dang, Anne M. Baranger, David L. Beveridge
Summary: In this study, we used MD simulations and molecular dynamics methods to investigate the unfolding process of the spliceosome protein U1A, revealing detailed molecular information and the transition state. The results showed that the unfolding pathway of U1A exhibits a high energy channel-like transition state, which is slightly different from the typical two-state behavior. These findings have important implications for understanding the structure and function of proteins.
Article
Biochemistry & Molecular Biology
Rajarshi Roy, Sayan Poddar, Md Fulbabu Sk, Parimal Kar
Summary: In this study, the conformational dynamics of complex glycans on the surface of HIV glycoprotein were investigated using molecular dynamics simulations. The results reveal the influence of adding complex branches on the overall glycan structural dynamics and provide insights into the flexibility and conformational changes of different glycan branches.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Biochemistry & Molecular Biology
Cullen Demakis, Matthew C. Childers, Valerie Daggett
Summary: This study uses high temperature unfolding simulations to explore the folding and unfolding pathways of the SH3 domain. Results show that SH3 domain proteins with different sequences can unfold through two main pathways, while certain structural characteristics remain conserved regardless of sequence. Disparate sequences can provide similar interactions that influence folding and lead to similar structures.
Article
Physics, Multidisciplinary
Yu-Hang Zhang, Zhen-Yong Xue, Hao Sun, Zhu-Wei Zhang, Hu Chen
Summary: There are significant differences in mechanical stability and unfolding dynamics among proteins with different structural compositions. Magnetic tweezers, which can precisely control forces on a pico-Newton scale, are suitable to measure force-induced conformation transitions of proteins. In this study, ACBP was stretched using magnetic tweezers and the unfolding forces at different loading rates were measured. The results showed that ACBP has an extraordinarily long unfolding distance and unfolding of α-helices is less cooperative than β-sheet structures.
ACTA PHYSICA SINICA
(2023)
Article
Biochemistry & Molecular Biology
Mayank Kumar, R. S. Rathore
Summary: The Ramachandran steric map is used to describe the conformation space of protein structures. This study focused on identifying disallowed spots in protein structures and found that certain residues tend to occur in disallowed conformations. Short loops and residues involved in interactions were particularly affected by conformational strain. Additionally, certain amino acids were found to have a higher tendency to occur in disallowed conformations.
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
(2023)
Article
Chemistry, Physical
Marcin Sobieraj, Piotr Setny
Summary: Constantly advancing computer simulations of bio-molecules provide a large amount of data that is challenging to interpret. In this study, Granger causality analysis is applied to analyze a molecular dynamics trajectory of a protein, revealing the importance of rearrangements in the hairpin turn region for protein folding and unfolding. The findings support the concept of zipperlike folding and demonstrate the potential of Granger causality analysis in biomolecular systems.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Biochemistry & Molecular Biology
Leonore Novak, Maria Petrosino, Daniele Santorelli, Roberta Chiaraluce, Valerio Consalvi, Alessandra Pasquo, Carlo Travaglini-Allocatelli
Summary: A Phi value analysis was conducted on BRD2(2) to investigate its folding pathway, revealing that the C-terminal region serves as the initial folding nucleus, with the N-terminal region consolidating its structure later in the process. This indicates a hierarchical mechanism of protein folding with non-native interactions playing a significant role.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Physical
Frederico Campos Freitas, Michelli Maldonado, Antonio Bento Oliveira Junior, Jose Nelson Onuchic, Ronaldo Junio de Oliveira
Summary: Biotin-labeled proteins are commonly used to study protein-protein interactions and proximity in living cells. However, the influence of biotinylation on aspects such as folding, binding, stability, and kinetics needs to be investigated further.
JOURNAL OF CHEMICAL PHYSICS
(2022)
Article
Biochemistry & Molecular Biology
Harutyun Sahakyan, Karen Nazaryan, Arcady Mushegian, Irina Sorokina
Summary: Molecular dynamics simulations were performed to study protein folding. By applying rotational force to the C-terminal amino acid while restricting the movement of the N-terminal amino acid, the folding of four protein domains was accelerated at least by an order of magnitude. These results suggest that external forces and constraints can bias the motions of the polypeptide and facilitate the attainment of stable fold.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biophysics
Cristina Paissoni, Sarita Puri, Iren Wang, Szu-Yu Chen, Carlo Camilloni, Shang-Te Danny Hsu
Summary: MJ0366 from Methanocaldococcus jannaschii is the smallest topologically knotted protein known to date, tying a trefoil knot by threading its C-terminal helix through a buttonhole formed by the remainder of the secondary structure elements. Experimental and computational results show that, despite the small size, the transition state of MJ0366 is formed at a very late stage of the folding reaction coordinate, following a polarized pathway.
BIOPHYSICAL JOURNAL
(2021)
Article
Chemistry, Physical
Mahdi Ghorbani, Samarjeet Prasad, Jeffery B. Klauda, Bernard R. Brooks
Summary: The study introduces a machine learning method, GMVAE, which can perform dimensionality reduction and clustering of biomolecular conformations effectively. The model shows potential in analyzing the free energy landscape of protein folding, with highly separated clusters corresponding to metastable states during folding.
JOURNAL OF CHEMICAL PHYSICS
(2021)
Article
Multidisciplinary Sciences
Lukas Rohland, Roman Kityk, Luka Smalinskaite, Matthias P. Mayer
Summary: The 70 kDa heat shock proteins (Hsp70s) are versatile molecular chaperones that assist in protein-folding processes. ATP and cochaperones induce structural rearrangements in Hsp70, with peptides causing larger changes and protein clients being more effective in stimulating ATP hydrolysis. The study provides insights into the mechanics, allostery, and dynamics of Hsp70 chaperones.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Biochemistry & Molecular Biology
Irina Artsimovitch, Cesar A. Ramirez-Sarmiento
Summary: Metamorphic proteins present unexpected paradigms in protein folding, as their sequences encode two alternative folds that can reversibly interconvert and trigger different cellular responses. This phenomenon may be common among proteins that need to respond to rapidly changing environments. This article summarizes the structural and functional evidence of RfaH as a metamorphic protein, describes the molecular mechanism and refolding pathways of its structural interconversion, and discusses ongoing efforts to identify signatures and general properties of the protein metamorphome.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2022)
Article
Biochemical Research Methods
Annie M. Westerlund, Akshay Sridhar, Leo Dahl, Alma Andersson, Anna-Yaroslava Bodnar, Lucie Delemotte
Summary: Calmodulin (CaM) is a calcium-sensing protein that regulates other proteins by binding them in a calcium-dependent manner. Trifluoperazine (TFP), an antipsychotic drug, inhibits the ability of CaM to bind and regulate other proteins. In this study, we used molecular dynamics simulations, Markov state modeling, and machine learning to understand how TFP binding to one domain of CaM prevents its association with other proteins. We found that TFP promotes the adoption of a conformation similar to the calcium-unbound form of CaM, affecting different structural and dynamic features depending on its binding orientation. Understanding TFP binding is a crucial step towards developing improved drugs that target CaM.
PLOS COMPUTATIONAL BIOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Ross J. Taylor, Mauricio Aguilar Rangel, Michael B. Geeson, Pietro Sormanni, Michele Vendruscolo, Goncalo J. L. Bernardes
Summary: Post-translational protein-protein conjugation allows for the production of bioconjugates that are not achievable through genetic fusion. This study describes a method using x-clamp-mediated cysteine arylation with pentafluorophenyl sulfonamide functional groups to prepare protein-protein conjugates. By computationally designing antibodies targeting the SARS-CoV-2 receptor binding domain and using the pi-clamp sequence, dimerization was achieved, resulting in a significant increase in binding. This strategy enables the construction of molecule-protein-protein conjugates with precise chemical control over the modification sites.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Multidisciplinary Sciences
Zenon Toprakcioglu, Ayaka Kamada, Thomas C. T. Michaels, Mengqi Xie, Johannes Krausser, Jiapeng Wei, Andela Saric, Michele Vendruscolo, Tuomas P. J. Knowles
Summary: Primary nucleation is the fundamental event in the formation of amyloid aggregates. This study demonstrates that interfaces can modulate nucleation by affecting the primary nucleation step. The strength of surface interactions plays a crucial role in regulating nucleation rates.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Cristina Olivieri, Geoffrey C. Li, Yingjie Wang, V. S. Manu, Caitlin Walker, Jonggul Kim, Carlo Camilloni, Alfonso De Simone, Michele Vendruscolo, David A. Bernlohr, Susan S. Taylor, Gianluigi Veglia
Summary: ATP-competitive inhibitors are a major class of drugs for protein kinases. Using protein kinase A as a model system, this study shows that different ATP-competitive inhibitors modulate substrate binding cooperativity by tuning the conformational entropy of the kinase. The findings propose a new paradigm for the discovery of ATP-competitive inhibitors based on their ability to modulate the allosteric coupling between nucleotide and substrate-binding sites.
Review
Multidisciplinary Sciences
Michele Vendruscolo, Monika Fuxreiter
Summary: Condensed states of proteins play crucial roles in the organization and function of cells, and disruptions of these states can lead to various diseases. This review analyzes the identification of targets for pharmacological interventions and explores opportunities for regulating aberrant protein condensation.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Attila Horvath, Michele Vendruscolo, Monika Fuxreiter
Summary: Mutations in TDP-43 can impact its cytotoxicity and facilitate the conversion between droplets and amyloid-containing aggregates.
Article
Biochemical Research Methods
Marc Oeller, Ryan Kang, Rosie Bell, Hannes Ausserwoger, Pietro Sormanni, Michele Vendruscolo
Summary: This article describes a computational method that incorporates the effect of pH on protein solubility predictions. The accuracy of these predictions is comparable to experimental methods, as demonstrated on various antibodies and proteins. This method, named CamSol 3.0, is now publicly available at https://www-cohsoftware.ch.cam.ac.uk/index.php/camsolph.
BRIEFINGS IN BIOINFORMATICS
(2023)
Article
Multidisciplinary Sciences
Alyssa Miller, Sean Chia, Zenon Toprakcioglu, Tuuli Hakala, Roman Schmid, Yaduo Feng, Tadas Kartanas, Ayaka Kamada, Michele Vendruscolo, Francesco Simone Ruggeri, Tuomas P. J. Knowles
Summary: In this study, a lab-on-a-chip spray approach was developed to combine rapid sample preparation, mixing, and deposition with nanoanalytical methods in chemistry and biology. This method provides enhanced spectroscopic sensitivity and single-molecule spatial resolution, allowing for multidimensional studies of heterogeneous biomolecular systems.
Review
Chemistry, Multidisciplinary
Ryan Limbocker, Nunilo Cremades, Roberta Cascella, Peter M. Tessier, Michele Vendruscolo, Fabrizio Chiti
Summary: The misfolding and aggregation of peptides and proteins into amyloid aggregates is a common feature of various protein misfolding diseases, including Alzheimer's disease and Parkinson's disease. Misfolded protein oligomers, which can form intermediates in the fibril formation process or be released by mature fibrils, are increasingly recognized as central to the development of these diseases. Despite challenges in studying these oligomers, researchers have developed methods to produce stable and reproducible populations for experimentation. These tools have provided insights into the structural determinants of oligomer toxicity and potential therapeutic strategies.
ACCOUNTS OF CHEMICAL RESEARCH
(2023)
Review
Pharmacology & Pharmacy
Michele Vendruscolo
Summary: Protein misfolding diseases, such as Alzheimer's and Parkinson's diseases, have a major impact on our healthcare systems and societies. This paper discusses drug discovery strategies to target protein misfolding and aggregation, including thermodynamic and kinetic approaches. There is a need for disease-modifying treatments to address the over 50 human disorders associated with protein misfolding and aggregation.
EXPERT OPINION ON DRUG DISCOVERY
(2023)
Review
Clinical Neurology
Mark R. Wilson, Sandeep Satapathy, Michele Vendruscolo
Summary: The proteostasis system regulates cellular processes of protein synthesis, folding, concentration, trafficking, and degradation. The mechanisms of extracellular proteostasis, particularly in the context of neurodegenerative diseases, are not well understood, but growing evidence suggests that impairment of this system may contribute to neuronal death.
NATURE REVIEWS NEUROLOGY
(2023)
Article
Biochemistry & Molecular Biology
Andras Hatos, Joao M. C. Teixeira, Susana Barrera-Vilarmau, Attila Horvath, Silvio C. E. Tosatto, Michele Vendruscolo, Monika Fuxreiter
Summary: Proteins form complex interactions in the cellular environment. The FuzPred server predicts their binding modes based on sequence without specifying the binding partners. The server also estimates the multiplicity of binding modes and visualizes different interaction behaviors on protein structures.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Multidisciplinary Sciences
Alyssa Miller, Jiapeng Wei, Sarah Meehan, Christopher M. Dobson, Mark E. Welland, David Klenerman, Michele Vendruscolo, Francesco Simone Ruggeri, Tuomas P. J. Knowles
Summary: Neurodegenerative diseases such as Alzheimer's disease are caused by protein misfolding and aggregation into amyloid fibrils. This study uses atomic force microscopy and statistical theory to characterize amyloid ring structures derived from the brains of AD patients and explains the diversity in the structures formed from protein aggregation. The results show that ex vivo protofibril chains possess greater flexibility than mature amyloid fibrils, allowing them to form end-to-end connections and shedding light on their role in disease.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Z. Faidon Brotzakis, Thomas Lohr, Steven Truong, Samuel Hoff, Massimiliano Bonomi, Michele Vendruscolo
Summary: In recent years, cryo-electron microscopy has made significant advancements in determining biomolecular structures at the atomic level. However, studying large systems with continuous dynamics using this method has been a challenge. To address this, the metadynamic electron microscopy metainference (MEMMI) method was developed, which combines cryo-EM density maps with prior information to determine the structure and dynamics of large heterogeneous systems. This method was applied to study the amyloid fibril dynamics of the islet amyloid polypeptide (IAPP), revealing interesting characteristics of the fibril's structural variability and liquid-like dynamics in the core region.
Article
Multidisciplinary Sciences
Christine M. Lim, Alicia Gonzalez Diaz, Monika Fuxreiter, Frank W. Pun, Alex Zhavoronkov, Michele Vendruscolo
Summary: This study presents an approach that combines the PandaOmics platform with the FuzDrop method to identify disease-associated proteins prone to protein phase separation (PPS). The validated targets for Alzheimer's disease suggest the potential of this approach in identifying therapeutic targets for diseases involving dysregulation of PPS.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Review
Physics, Applied
Thomas C. T. Michaels, Daoyuan Qian, Andela Saric, Michele Vendruscolo, Sara Linse, Tuomas P. J. Knowles
Summary: This Review discusses the general protein self-assembly behavior of amyloid fibrils, which is associated with functional biology and the development of diseases such as Alzheimer and Parkinson diseases. It summarizes recent progress in describing the biophysical features of amyloid self-assembly as a nucleation-and-growth process, highlighting the role of secondary nucleation. The Review also outlines non-classical aspects of aggregate formation and discusses their implications for understanding and modulating protein assembly pathways.
NATURE REVIEWS PHYSICS
(2023)
Article
Biochemistry & Molecular Biology
Ankita Chadda, Alexander G. Kozlov, Binh Nguyen, Timothy M. Lohman, Eric A. Galburt
Summary: In this study, it was found that the DNA damage response in Mycobacterium tuberculosis differs from well-studied model bacteria. The DNA repair helicase UvrD1 in Mtb is activated through a redox-dependent process and is closely associated with the homo-dimeric Ku protein. Additionally, Ku protein is shown to stimulate the helicase activity of UvrD1.
JOURNAL OF MOLECULAR BIOLOGY
(2024)