A5057978306- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Enzyme Structure and Function
- Animal testing and alternatives
- Effects and risks of endocrine disrupting chemicals
- Alzheimer's disease research and treatments
- Metabolomics and Mass Spectrometry Studies
- Carcinogens and Genotoxicity Assessment
- Advanced NMR Techniques and Applications
- Glycosylation and Glycoproteins Research
- RNA and protein synthesis mechanisms
- Cholinesterase and Neurodegenerative Diseases
- Monoclonal and Polyclonal Antibodies Research
- Microbial Metabolic Engineering and Bioproduction
- Mass Spectrometry Techniques and Applications
- Viral Infectious Diseases and Gene Expression in Insects
- Chemical Safety and Risk Management
- Parkinson's Disease Mechanisms and Treatments
- Cell Adhesion Molecules Research
- Chemistry and Chemical Engineering
- Electrochemical sensors and biosensors
- Proteins in Food Systems
- DNA Repair Mechanisms
- Advanced Proteomics Techniques and Applications
- Genomics and Chromatin Dynamics
Unilever (United Kingdom)
2020-2024
University of Bedfordshire
2024
Vitenparken
2024
University of Cambridge
2014-2019
University College Dublin
2009-2017
Abstract Next-Generation Risk Assessment is defined as an exposure-led, hypothesis-driven risk assessment approach that integrates new methodologies (NAMs) to assure safety without the use of animal testing. These principles were applied a hypothetical 0.1% coumarin in face cream and body lotion. For purpose evaluating NAMs, existing human data on excluded. Internal concentrations (plasma Cmax) estimated using physiologically based kinetic model for dermally coumarin. Systemic toxicity was...
Understanding the connection between protein structure and function requires a quantitative understanding of electrostatic effects. Structure-based calculations are essential for this purpose, but their use has been limited by long-standing discussion on which value to dielectric constants (ε(eff) ε(p)) required in Coulombic Poisson-Boltzmann models. The currently used values ε(eff) ε(p) essentially empirical parameters calibrated against thermodynamic properties that indirect measurements...
Significance Protein biosynthesis is carried out by ribosomes, the macromolecular machines present in all kingdoms of life. Aided molecular chaperones, nascent proteins can begin to fold while emerging from ribosome. Achieving their native fold, and avoiding misfolding, thereby crucial for fate newly synthesized proteins. The details this fundamental process, however, are poorly understood. In work we develop a combined NMR simulation approach characterize behavior during α-synuclein (αSyn),...
An important question in toxicological risk assessment is whether non-animal new approach methodologies (NAMs) can be used to make safety decisions that are protective of human health, without being overly conservative. In this work, we propose a core NAM toolbox and workflow for conducting systemic assessments adult consumers. We also present an evaluating how useful the by benchmarking against historical decisions. The includes physiologically based kinetic (PBK) models estimate Cmax...
Protein inter-residue contact maps provide a translation and rotation invariant topological representation of protein. They can be used as an intermediary step in protein structure predictions. However, the prediction represents unbalanced problem far fewer examples contacts than non-contacts exist structure. In this study we explore possibility completely eliminating nature map by predicting real-value distances between residues. Predicting full distance applying them predictions has been...
Site-specific histone ubiquitylation plays a central role in orchestrating the response to DNA double-strand breaks (DSBs). DSBs elicit cascade of events controlled by ubiquitin ligase RNF168, which promotes accumulation repair factors such as 53BP1 and BRCA1 on chromatin flanking break site. RNF168 also its own accumulation, that paralog RNF169, but how they recognize ubiquitylated is unknown. Using methyl-TROSY solution NMR spectroscopy molecular dynamics simulations, we present an atomic...
New Approach Methodologies (NAMs) promise to offer a unique opportunity enable human-relevant safety decisions be made without the need for animal testing in context of exposure-driven Next Generation Risk Assessment (NGRA). Protecting human health against potential effects chemical may have on embryo-foetal development and/or aspects reproductive biology using NGRA is particularly challenging. These are not single endpoint or and risk assessments traditionally relied data from Developmental...
The first Stakeholder Network Meeting of the EU Horizon 2020-funded ONTOX project was held on 13–14 March 2023, in Brussels, Belgium. discussion centred around identifying specific challenges, barriers and drivers relation to implementation non-animal new approach methodologies (NAMs) probabilistic risk assessment (PRA), order help address issues rank them according their associated level difficulty. aims advance chemical humans, without use animal testing, by developing NAMs PRA line with...
Abstract Post mortem biochemical staging of Alzheimer’s disease is currently based on immunochemical analysis brain slices with the AT8 antibody. The epitope described around pSer 202 /pThr 205 region hyperphosphorylated form neuronal protein tau. In this study, NMR spectroscopy was used to precisely map phosphorylated tau, and derive its defining structural features by a combination analyses molecular dynamics. A particular turn conformation stabilized hydrogen bond Thr residue amide proton...
The nucleation-condensation mechanism represents a major paradigm to understand the folding process of many small globular proteins. Although substantial evidence has been acquired for this mechanism, it remained very challenging characterize initial events leading formation nucleus. To achieve goal, we used combination relaxation dispersion NMR spectroscopy and molecular dynamics simulations determine ensembles conformations corresponding denatured, transition, native states in activation...
Abstract pH‐induced chemical shift perturbations (CSPs) can be used to study pH‐dependent conformational transitions in proteins. Recently, an elegant principal component analysis (PCA) algorithm was developed and the structural bovine β‐lactoglobulin (βLG) by analyzing its NMR pH‐titration spectra. Here, we augment this method filtering out changes that stem from effects are electrostatic nature. Specifically, examine how many CSPs explained purely arising titrational events βLG. The...
It has been recently shown that the coarse-graining of structures polypeptide chains as self-avoiding tubes can provide an effective representation conformational space proteins. In order to fully exploit opportunities offered by such a ‘tube model’ approach, we present here strategy combine it with molecular dynamics simulations. This is based on incorporation ‘CamTube’ force field into Gromacs package. By considering case 60-residue polyvaline chain, show CamTube simulations...
Lymphocyte function-associated antigen 1 (LFA-1) is an integrin that transmits information in two directions across the plasma membrane of leukocytes, so-called outside-in and inside-out signaling mechanisms. To investigate structural basis these mechanisms, we studied conformational space apo I-domain using replica-averaged metadynamics simulations combination with nuclear magnetic resonance chemical shifts. We thus obtained a free energy landscape reveals existence three substates this...
GH-18 chitinases are chitinolytic enzymes, primarily responsible for the recycling of insoluble chitin biomaterials. These enzymes contain three invariant acidic active-site residues within a DXDXE motif, which play synergistic role in catalytic cycle degradation. We employed pKa calculation approach to approximate protonation states D1, D2, and E motif 75 chitinases. Theoretical pH-activity profiles these were subsequently constructed compared with experimentally determined profiles. data...
Next Generation Risk Assessment (NGRA) is an exposure-led approach to safety assessment that uses New Approach Methodologies (NAMs). Application of NGRA has been largely restricted assessments consumer use cosmetics and not currently implemented in occupational assessments, e.g. under EU REACH. By contrast, a large proportion regulatory worker are underpinned by toxicological studies using experimental animals. Consequently, represents area would benefit from increasing application decision...
Abstract For many years, a method that allowed systemic toxicity safety assessments to be conducted without generating new animal test data, seemed out of reach. However, several different research groups and regulatory authorities are beginning use variety in silico, chemico vitro techniques inform decisions. To manage this transition animal-free responsibly, it is important ensure the level protection offered by assessment based on approach methodologies (NAMs), at least as high provided...