A5040445576- SARS-CoV-2 and COVID-19 Research
- Receptor Mechanisms and Signaling
- Nicotinic Acetylcholine Receptors Study
- Photosynthetic Processes and Mechanisms
- Protein Structure and Dynamics
- Photoreceptor and optogenetics research
- Lipid Membrane Structure and Behavior
- COVID-19 and healthcare impacts
- Influenza Virus Research Studies
- Spectroscopy and Quantum Chemical Studies
- Bacterial Genetics and Biotechnology
- RNA and protein synthesis mechanisms
- Computational Drug Discovery Methods
- Drug Transport and Resistance Mechanisms
- DNA and Nucleic Acid Chemistry
- Antibiotic Resistance in Bacteria
- Cardiac, Anesthesia and Surgical Outcomes
- Trauma and Emergency Care Studies
- Bacteriophages and microbial interactions
- Cystic Fibrosis Research Advances
- Ion channel regulation and function
- Coffee research and impacts
- thermodynamics and calorimetric analyses
- Single-cell and spatial transcriptomics
- Cancer therapeutics and mechanisms
University of Bristol
2017-2025
University of California, San Diego
2024
Max Planck-Bristol Centre for Minimal Biology
2024
Universidade Nova de Lisboa
2005-2023
University of Lisbon
2023
Bridge University
2023
National Research Council
2023
Universidade do Porto
2023
Universidad de Granada
2023
Instituto de Biologia Experimental e Tecnológica
2017
Understanding allostery in enzymes and tools to identify it offer promising alternative strategies inhibitor development. Through a combination of equilibrium nonequilibrium molecular dynamics simulations, we allosteric effects communication pathways two prototypical class A β-lactamases, TEM-1 KPC-2, which are important determinants antibiotic resistance. The simulations reveal operating over distances 30 Å or more. Propagation the signal occurs through cooperative coupling loop dynamics....
We seek to completely revise current models of airborne transmission respiratory viruses by providing never-before-seen atomic-level views the SARS-CoV-2 virus within a aerosol. Our work dramatically extends capabilities multiscale computational microscopy address significant gaps that exist in experimental methods, which are limited their ability interrogate aerosols at atomic/molecular level and thus obscure our understanding transmission. demonstrate how integrated data-driven platform...
The SARS-CoV-2 main protease (M
Abstract As the global burden of SARS-CoV-2 infections escalates, so does evolution viral variants with increased transmissibility and pathology. In addition to this entrenched diversity, RNA viruses can also display genetic diversity within single infected hosts co-existing evolving differently in distinct cell types. The BriSΔ variant, originally identified as a subpopulation from isolate hCoV-19/England/02/2020, comprises spike an eight amino-acid deletion encompassing furin recognition...
Protein functions are dynamically regulated by allostery, which enables conformational communication even between faraway residues, and expresses itself in many forms, akin to different "languages": allosteric control pathways predominating an unperturbed protein often unintuitively reshaped whenever biochemical perturbations arise (e.g., mutations). To accurately model unbiased molecular dynamics (MD) simulations require integration with a reliable method able to, e.g., detect incipient...
The target for humoral immunity, SARS-CoV-2 spike glycoprotein, has become the focus of vaccine research and development. Previous work demonstrated that N-terminal domain (NTD) binds biliverdin-a product heme catabolism-causing a strong allosteric effect on activity subset neutralizing antibodies. Herein, we show glycoprotein is also able to bind (KD = 0.5 ± 0.2 μM). Molecular modeling indicated group fits well within same pocket NTD. Lined by aromatic hydrophobic residues (W104, V126,...
Poisson−Boltzmann (PB) models are a fast and common tool for studying electrostatic processes in proteins, particularly their ionization equilibrium (protonation and/or reduction), often yielding quite good results when compared with more detailed models. Yet, they conceptually very simple necessarily approximate, empirical character being most evident it comes to the choice of dielectric constant assigned protein region. The present study analyzes several factors affecting ability PB-based...
The SARS-CoV-2 spike protein is the first contact point between virus and host cells mediates membrane fusion. Recently, a fatty acid binding site was identified in (Toelzer
The electron-conducting circuitry of life represents an as-yet untapped resource exquisite, nanoscale biomolecular engineering. Here, we report the characterization and structure a de novo diheme "maquette" protein, 4D2, which subsequently use to create expanded, modular platform for heme protein design. A well-folded monoheme variant was created by computational redesign, then utilized experimental validation continuum electrostatic redox potential calculations. This demonstrates how...
Abstract Nature has evolved diverse electron transport proteins and multiprotein assemblies essential to the generation transduction of biological energy. However, substantially modifying or adapting these for user‐defined applications gain fundamental mechanistic insight can be hindered by their inherent complexity. De novo protein design offers an attractive route stripping away this confounding complexity, enabling us probe workings bioenergetic systems, while providing robust, modular...
The trimeric spike protein plays an essential role in the SARS-CoV-2 virus lifecycle, facilitating entry through binding to cellular receptor angiotensin-converting enzyme 2 (ACE2) and mediating viral-host membrane fusion. contains a fatty acid (FA) site at interface between two neighbouring receptor-binding domains. This site, also found some other coronaviruses, binds free acids such as linoleic acid. Binding this locks non-infectious, closed conformation. is coupled functionally important...
ATP-Binding Cassette (ABC) transporters are ubiquitous membrane proteins that use energy from ATP binding or/and hydrolysis to actively transport allocrites across membranes. In this study, we identify ATP-hydrolysis induced conformational changes in a complete ABC exporter (Sav1866) Staphylococcus aureaus, using molecular dynamics (MD) simulations. By performing MD simulations on the and ADP+IP bound states, consequences of hydrolysis, showing major rearrangements not restricted NBDs, but...
ABC transporters are a large and important family of membrane proteins involved in substrate transport across the membrane. The transported substrates quite diverse, ranging from monatomic ions to biomolecules. Consequently, some biomedically relevant situations, genetic diseases multidrug resistance. most conserved domains nucleotide binding (NBDs), which form dimer responsible for hydrolysis ATP, concomitantly with translocation. To elucidate how ATP structurally affects NBD dimer,...
Nicotinic acetylcholine receptors (nAChRs) modulate synaptic activity in the central nervous system. The α7 subtype, particular, has attracted considerable interest drug discovery as a target for several conditions, including Alzheimer's disease and schizophrenia. Identifying agonist-induced structural changes underlying nAChR activation is fundamentally important understanding biological function rational design. Here, extensive equilibrium nonequilibrium molecular dynamics simulations,...
Differentiating nicotinic acetylcholine receptors (nAChR) to target the high-affinity nicotine α4β2 subtype is a major challenge in developing effective addiction therapies. Although cytisine 1 and varenicline 2 (current smoking-cessation agents) are partial agonists of α4β2, these drugs display full agonism at α7 nAChR subtype. Site-specific modification (−)-cytisine via Ir-catalyzed C‒H activation provides access C(10) variants 6–10, 13, 14, 17, 20, 22, docking studies reveal that...
Transport of proteins across and into membranes is a fundamental biological process with the vast majority being conducted by ubiquitous Sec machinery. In bacteria, this usually achieved when SecY-complex engages cytosolic ATPase SecA (secretion) or translating ribosomes (insertion). Great strides have been made towards understanding mechanism protein translocation. Yet, important questions remain - notably, nature individual steps that constitute transport, how proton-motive force (PMF)...
Abstract The SARS-CoV-2 spike protein contains a functionally important fatty acid (FA) binding site, which is also found in some other coronaviruses, e.g. SARS-CoV and MERS-CoV. occupancy of the FA site by linoleic (LA) reduces infectivity ‘locking’ less infectious conformation. Here, we use dynamical-nonequilibrium molecular dynamics (D-NEMD) simulations to compare allosteric responses variants LA removal. D-NEMD show that coupled functional regions protein, receptor-binding motif (RBM),...