108 results on '"Dhulesia, A"'
Search Results
2. Experimental free energy surfaces reveal the mechanisms of maintenance of protein solubility
- Author
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De Simone, Alfonso, Dhulesia, Anne, Soldi, Gemma, Vendruscolo, Michele, Hsu, Shang-Te Danny, Chiti, Fabrizio, and Dobson, Christopher M.
- Published
- 2011
3. Structure of a low-population intermediate state in the release of an enzyme product
- Author
-
Alfonso De Simone, Francesco A Aprile, Anne Dhulesia, Christopher M Dobson, and Michele Vendruscolo
- Subjects
NMR spectroscopy ,residual dipolar coupling ,molecular dynamics simulation ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Enzymes can increase the rate of biomolecular reactions by several orders of magnitude. Although the steps of substrate capture and product release are essential in the enzymatic process, complete atomic-level descriptions of these steps are difficult to obtain because of the transient nature of the intermediate conformations, which makes them largely inaccessible to standard structure determination methods. We describe here the determination of the structure of a low-population intermediate in the product release process by human lysozyme through a combination of NMR spectroscopy and molecular dynamics simulations. We validate this structure by rationally designing two mutations, the first engineered to destabilise the intermediate and the second to stabilise it, thus slowing down or speeding up, respectively, product release. These results illustrate how product release by an enzyme can be facilitated by the presence of a metastable intermediate with transient weak interactions between the enzyme and product.
- Published
- 2015
- Full Text
- View/download PDF
4. Hsp70 oligomerization is mediated by an interaction between the interdomain linker and the substrate-binding domain.
- Author
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Francesco A Aprile, Anne Dhulesia, Florian Stengel, Cintia Roodveldt, Justin L P Benesch, Paolo Tortora, Carol V Robinson, Xavier Salvatella, Christopher M Dobson, and Nunilo Cremades
- Subjects
Medicine ,Science - Abstract
Oligomerization in the heat shock protein (Hsp) 70 family has been extensively documented both in vitro and in vivo, although the mechanism, the identity of the specific protein regions involved and the physiological relevance of this process are still unclear. We have studied the oligomeric properties of a series of human Hsp70 variants by means of nanoelectrospray ionization mass spectrometry, optical spectroscopy and quantitative size exclusion chromatography. Our results show that Hsp70 oligomerization takes place through a specific interaction between the interdomain linker of one molecule and the substrate-binding domain of a different molecule, generating dimers and higher-order oligomers. We have found that substrate binding shifts the oligomerization equilibrium towards the accumulation of functional monomeric protein, probably by sequestering the helical lid sub-domain needed to stabilize the chaperone: substrate complex. Taken together, these findings suggest a possible role of chaperone oligomerization as a mechanism for regulating the availability of the active monomeric form of the chaperone and for the control of substrate binding and release.
- Published
- 2013
- Full Text
- View/download PDF
5. Networks of Coupled Rotators: Relationship between structures and internal dynamics in metal-binding proteins: Applications to apo- and holo-calbindin
- Author
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Dhulesia, Anne, Abergel, Daniel, and Bodenhausen, Geoffrey
- Subjects
Calcium-binding proteins -- Chemical properties ,Calcium-binding proteins -- Structure ,Chemistry - Abstract
The relationship between the structures and internal dynamics of the C[a.sup.2-] binding protein calbindin is analyzed, which is normally based on the newly developed Networks of Coupled Rotators (NCRs). The incorporation into the NCR model proves the presence of weak interactions between the calcium and oxygen atoms and hence shows that it can be used for the study of many other systems.
- Published
- 2007
6. A non-natural variant of human lysozyme (I59T) mimics the in vitro behaviour of the I56T variant that is responsible for a form of familial amyloidosis
- Author
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Hagan, Christine L., Johnson, Russell J.K., Dhulesia, Anne, Dumoulin, Mireille, Dumont, Janice, De Genst, Erwin, Christodoulou, John, Robinson, Carol V., Dobson, Christopher M., and Kumita, Janet R.
- Published
- 2010
- Full Text
- View/download PDF
7. Hydrodynamics and efficiency of distillation trays
- Author
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Dhulesia, H. A.
- Subjects
660 ,Chemical engineering - Published
- 1980
8. Inhibition of α-Synuclein Fibril Elongation by Hsp70 Is Governed by a Kinetic Binding Competition between α-Synuclein Species
- Author
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Tuomas P. J. Knowles, Janet R. Kumita, Anne Dhulesia, Christopher M. Dobson, Giuliana Fusco, Paolo Arosio, Paolo Tortora, Francesco A. Aprile, Serene W. Chen, Nunilo Cremades, Michele Vendruscolo, Ministerio de Economía y Competitividad (España), Aprile, Francesco [0000-0002-5040-4420], Kumita, Janet [0000-0002-3887-4964], Knowles, Tuomas [0000-0002-7879-0140], Vendruscolo, Michele [0000-0002-3616-1610], Apollo - University of Cambridge Repository, Aprile, F, Arosio, P, Fusco, G, Chen, S, Kumita, J, Dhulesia, A, Tortora, P, Knowles, T, Vendruscolo, M, Dobson, C, and Cremades, N
- Subjects
0301 basic medicine ,Kinetics ,Cell ,Biology ,Protein aggregation ,Fibril ,Biochemistry ,Binding, Competitive ,Protein Structure, Secondary ,Substrate Specificity ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Humans ,HSP70 Heat-Shock Proteins ,Kinetic ,Alpha-synuclein ,HSP70 Heat-Shock Protein ,Binding protein ,Neurodegeneration ,medicine.disease ,Hsp70 ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Biophysics ,alpha-Synuclein ,Protein Multimerization ,030217 neurology & neurosurgery ,Human - Abstract
The Hsp70 family of chaperones plays an essential role in suppressing protein aggregation in the cell. Here we investigate the factors controlling the intrinsic ability of human Hsp70 to inhibit the elongation of amyloid fibrils formed by the Parkinson's disease-related protein α-synuclein. Using kinetic analysis, we show that Hsp70 binds preferentially to α-synuclein fibrils as a consequence of variations in the association and dissociation rate constants of binding to the different aggregated states of the protein. Our findings illustrate the importance of the kinetics of binding of molecular chaperones, and also of potential therapeutic molecules, in the efficient suppression of specific pathogenic events linked to neurodegeneration.
- Published
- 2017
9. Application of Lysine-specific Labeling to Detect Transient Interactions Present During Human Lysozyme Amyloid Fibril Formation
- Author
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Ahn, Minkoo, Waudby, Christopher A., Bernardo-Gancedo, Ana, De Genst, Erwin, Dhulesia, Anne, Salvatella, Xavier, Christodoulou, John, Dobson, Christopher M., Kumita, Janet R., Ahn, Minkoo [0000-0001-9131-7334], Waudby, Christopher A [0000-0001-7810-3753], Salvatella, Xavier [0000-0002-8371-4185], Kumita, Janet R [0000-0002-3887-4964], and Apollo - University of Cambridge Repository
- Subjects
Amyloid ,Lysine ,lcsh:R ,lcsh:Medicine ,Humans ,lcsh:Q ,Muramidase ,Spin Labels ,bcs ,lcsh:Science ,Nuclear Magnetic Resonance, Biomolecular ,Article ,Protein Structure, Secondary - Abstract
Populating transient and partially unfolded species is a crucial step in the formation and accumulation of amyloid fibrils formed from pathogenic variants of human lysozyme linked with a rare but fatal hereditary systemic amyloidosis. The partially unfolded species possess an unstructured β-domain and C-helix with the rest of the α-domain remaining native-like. Here we use paramagnetic relaxation enhancement (PRE) measured by NMR spectroscopy to study the transient intermolecular interactions between such intermediate species. Nitroxide spin labels, introduced specifically at three individual lysine residues, generate distinct PRE profiles, indicating the presence of intermolecular interactions between residues within the unfolded β-domain. This study describes the applicability to PRE NMR measurements of selective lysine labeling, at different sites within a protein, as an alternative to the introduction of spin labels via engineered cysteine residues. These results reveal the importance of the β-sheet region of lysozyme for initiating self-assembly into amyloid fibrils.
- Published
- 2018
- Full Text
- View/download PDF
10. Hsp70 oligomerization is mediated by an interaction between the interdomain linker and the substrate-binding domain
- Author
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Paolo Tortora, Carol V. Robinson, Francesco A. Aprile, Christopher M. Dobson, Anne Dhulesia, Florian Stengel, Cintia Roodveldt, Nunilo Cremades, Xavier Salvatella, Justin L. P. Benesch, Ministero dell'Istruzione, dell'Università e della Ricerca, University of Cambridge, Ministerio de Sanidad, Servicios Sociales e Igualdad (España), Instituto de Salud Carlos III, European Commission, Royal Society (UK), Human Frontier Science Program, Aprile, F, Dhulesia, A, Stengel, F, Roodveldt, C, Benesch, J, Tortora, P, Robinson, C, Salvatella, X, Dobson, C, and Cremades, N
- Subjects
Spectrometry, Mass, Electrospray Ionization ,lcsh:Medicine ,Plasma protein binding ,Polymerization ,Hsp70 ,oligomerization ,Protein–protein interaction ,03 medical and health sciences ,chemistry.chemical_compound ,Protein structure ,Heat shock protein ,Humans ,HSP70 Heat-Shock Proteins ,Binding site ,lcsh:Science ,mass spectrometry ,030304 developmental biology ,0303 health sciences ,Binding Sites ,Multidisciplinary ,biology ,Chemistry ,lcsh:R ,030302 biochemistry & molecular biology ,BIO/10 - BIOCHIMICA ,Protein Structure, Tertiary ,Monomer ,Biochemistry ,Chaperone (protein) ,biology.protein ,Biophysics ,lcsh:Q ,fluorescence ,Linker ,Molecular Chaperones ,Protein Binding ,Research Article - Abstract
Oligomerization in the heat shock protein (Hsp) 70 family has been extensively documented both in vitro and in vivo, although the mechanism, the identity of the specific protein regions involved and the physiological relevance of this process are still unclear. We have studied the oligomeric properties of a series of human Hsp70 variants by means of nanoelectrospray ionization mass spectrometry, optical spectroscopy and quantitative size exclusion chromatography. Our results show that Hsp70 oligomerization takes place through a specific interaction between the interdomain linker of one molecule and the substrate-binding domain of a different molecule, generating dimers and higher-order oligomers. We have found that substrate binding shifts the oligomerization equilibrium towards the accumulation of functional monomeric protein, probably by sequestering the helical lid sub-domain needed to stabilize the chaperone: substrate complex. Taken together, these findings suggest a possible role of chaperone oligomerization as a mechanism for regulating the availability of the active monomeric form of the chaperone and for the control of substrate binding and release. © 2013 Aprile et al., FAA was recipient of a graduate fellowship from the Italian Ministry of Education, University and Research. AD is grateful for support from Murray Edwards College, Cambridge, through a Junior Research Fellowship. FS is a Sir Henry Wellcome Fellow. CR acknowledges financial support by the Spanish Ministry of Health according to the 'Plan Nacional de I+D+I 2008-2011', through ISCIII with cofunding by FEDER (CP10/00527). JLPB is a Royal Society University Research Fellow. FAA and PT are grateful for support from Regione Lombardia (NEDD and >Network Tecnologico integrato per lo studio proteomico e trascrittomico di malattie neurodegenerative correlate a deposizioni di amiloidi>). CMD acknowledges support from BBSRC (BB/E019927/1), the Wellcome Trust (094425/Z/10/Z), the European Commission (project LSHM-CT-2006-037525). NC acknowledges support from Human Frontiers Science Program (HFSP) through a Long-term Fellowship (LT000795/2009).
- Published
- 2016
11. The significance of the location of mutations for the native-state dynamics of human Lysozyme
- Author
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Ahn, M, Hagan, CL, Bernardo-Gancedo, A, De Genst, E, Newby, FN, Christodoulou, J, Dhulesia, A, Dumoulin, M, Robinson, CV, Dobson, CM, Kumita, JR, Ahn, Minkoo [0000-0001-9131-7334], Kumita, Janet [0000-0002-3887-4964], and Apollo - University of Cambridge Repository
- Subjects
Models, Molecular ,Amyloid ,Protein Domains ,Enzyme Stability ,Mutation ,Biophysics ,Humans ,Muramidase ,Protein Multimerization ,bcs ,Protein Structure, Secondary - Abstract
The conversion of human lysozyme into amyloid fibrils is associated with a rare but fatal hereditary form of nonneuropathic systemic amyloidosis. The accumulation of large amounts of aggregated protein is thought to be initiated by the formation of transient intermediate species of disease-related lysozyme variants, essentially due to the loss of global cooperativity under physiologically relevant conditions. Interestingly, all five naturally occurring, amyloidogenic, single-point mutations are located in the β-domain of lysozyme, the region that is predominantly unfolded during the formation of the transient intermediate species. Given the lack of known naturally occurring, amyloidogenic, single-point mutations in the α-domain, we chose three specific mutations to address the effects that location may have on native-state dynamics, as studied by hydrogen-deuterium (HD) exchange experiments analyzed by NMR spectroscopy, and mass spectrometry. We compared the effect of a destabilizing α-domain mutation (I23A) with that of the well-characterized I59T β-domain variant. We also investigated the effect of a mutation that has minor effects on native-state stability at the domain interface (I56V) and compared it with that of a variant with similar stability within the C-helix (I89V). We show that when variants have similar reduced native-state stabilities, the location of the mutation (I23A versus I59T) is crucial to the native-state dynamics, with the α-domain mutation having a significantly lower ability to populate transient intermediate species under physiologically relevant conditions. Interestingly, the mutation at the interface (I56V) has a greater effect in facilitating the formation of transient intermediate species at elevated temperatures compared with the variants containing α-domain mutations, even though this mutation results in only minor changes to the native-state stability of lysozyme. These findings reveal that the location of specific mutations is an important factor in determining the native-state dynamical properties of human lysozyme in the context of its propensity to populate the aggregation-prone transient intermediate species associated with pathogenic amyloid formation.
- Published
- 2016
12. Local Cooperativity in an Amyloidogenic State of Human Lysozyme Observed at Atomic Resolution
- Author
-
Dhulesia, Anne, Cremades, Nunilo, Kumita, Janet R., Hsu, Shang-Te Danny, Mossuto, Maria F., Dumoulin, Mireille, Nietlispach, Daniel, Akke, Mikael, Salvatella, Xavier, and Dobson, Christopher M.
- Abstract
The partial unfolding of human lysozyme underlies its conversion from the soluble state into amyloid fibrils observed in a fatal hereditary form of systemic amyloidosis. To understand the molecular origins of the disease, it is critical to characterize the structural and physicochemical properties of the amyloidogenic states of the protein. Here we provide a high-resolution view of the unfolding process at low pH for three different lysozyme variants, the wild-type protein and the mutants I56T and I59T, which show variable stabilities and propensities to aggregate in vitro. Using a range of biophysical techniques that includes differential scanning calorimetry and nuclear magnetic resonance spectroscopy, we demonstrate that thermal unfolding under amyloidogenic solution conditions involves a cooperative loss of native tertiary structure, followed by progressive unfolding of a compact, molten globule-like denatured state ensemble as the temperature is increased. The width of the temperature window over which the denatured ensemble progressively unfolds correlates with the relative amyloidogenicity and stability of these variants, and the region of lysozyme that unfolds first maps to that which forms the core of the amyloid fibrils formed under similar conditions. Together, these results present a coherent picture at atomic resolution of the initial events underlying amyloid formation by a globular protein.
- Published
- 2024
- Full Text
- View/download PDF
13. Structure of a low-population intermediate state in the release of an enzyme product
- Author
-
Christopher M. Dobson, Alfonso De Simone, Francesco A. Aprile, Michele Vendruscolo, Anne Dhulesia, De Simone, A., Aprile, F. A., Dhulesia, A., Dobson, C. M., and Vendruscolo, M.
- Subjects
Models, Molecular ,QH301-705.5 ,Science ,Population ,Short Report ,Biology ,010402 general chemistry ,01 natural sciences ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,chemistry.chemical_compound ,NMR spectroscopy ,biophysics ,structural biology ,Humans ,human ,Biology (General) ,education ,Muramidase ,residual dipolar coupling ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,education.field_of_study ,General Immunology and Microbiology ,General Neuroscience ,Substrate (chemistry) ,General Medicine ,molecular dynamics simulations ,Biophysics and Structural Biology ,0104 chemical sciences ,Enzyme binding ,molecular dynamics simulation ,Enzyme ,Biochemistry ,chemistry ,Structural biology ,Biophysics ,Medicine ,Thermodynamics ,Peptidoglycan ,Lysozyme ,residual dipolar couplings ,Trisaccharides - Abstract
Enzymes can increase the rate of biomolecular reactions by several orders of magnitude. Although the steps of substrate capture and product release are essential in the enzymatic process, complete atomic-level descriptions of these steps are difficult to obtain because of the transient nature of the intermediate conformations, which makes them largely inaccessible to standard structure determination methods. We describe here the determination of the structure of a low-population intermediate in the product release process by human lysozyme through a combination of NMR spectroscopy and molecular dynamics simulations. We validate this structure by rationally designing two mutations, the first engineered to destabilise the intermediate and the second to stabilise it, thus slowing down or speeding up, respectively, product release. These results illustrate how product release by an enzyme can be facilitated by the presence of a metastable intermediate with transient weak interactions between the enzyme and product. DOI: http://dx.doi.org/10.7554/eLife.02777.001, eLife digest Enzymes are proteins that catalyse biochemical reactions. They bind to their target molecules—known as substrates—and help to change them to make ‘products’. Afterwards, the products are released and the enzymes are free to bind to the next molecules. To perform this activity, an enzyme can change its structure several times, but it has been challenging to characterise the intermediate shapes because of their transient nature. De Simone et al. took advantage of a technique called nuclear magnetic resonance spectroscopy to get a better look at the structures adopted by the human enzyme lysozyme. This enzyme helps to protect us from bacterial infections because it breaks the links between peptidoglycan molecules, which make up the wall that surrounds bacterial cells. The experiments show that two ‘arms’ in the lysozyme structure move to create an intermediate shape during the final step—the release of the product—in the chemical reaction. This type of flexibility gives the enzyme the ability to tightly bind the peptidoglycan at the start and to let go of the product when the chemical reaction is complete. Next, to confirm their findings, De Simone et al. examined what happened when they introduced particular mutations in the gene that makes lysozyme. The first mutation was meant to destabilise the intermediate shape of the enzyme, which resulted in the enzyme binding more tightly to the peptidoglycan in the final step and releasing it more slowly. A second mutation was made to stabilize the structure of the intermediate shape, which, as expected, allowed lysozyme to release the peptidoglycan more quickly. De Simone et al.'s findings explain how intermediate shapes can be involved in the release of the product from lysozyme and other enzymes. The next challenges will be to characterise the structure of the intermediate shape that binds to the substrate and, more generally, to extend this type of approach to other enzymes. DOI: http://dx.doi.org/10.7554/eLife.02777.002
- Published
- 2014
14. Application of Lysine-specific Labeling to Detect Transient Interactions Present During Human Lysozyme Amyloid Fibril Formation
- Author
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Ahn, Minkoo, primary, Waudby, Christopher A., additional, Bernardo-Gancedo, Ana, additional, De Genst, Erwin, additional, Dhulesia, Anne, additional, Salvatella, Xavier, additional, Christodoulou, John, additional, Dobson, Christopher M., additional, and Kumita, Janet R., additional
- Published
- 2017
- Full Text
- View/download PDF
15. Predicting conformational entropy of bond vectors in proteins by networks of coupled rotators.
- Author
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Dhulesia, Anne, Bodenhausen, Geoffrey, and Abergel, Daniel
- Subjects
- *
ENTROPY , *CARRIER proteins , *THERMODYNAMICS , *CALCIUM in the body , *BODY composition - Abstract
In this article, a formal expression for the conformational entropy of a bond vector in a protein is derived using the networks of coupled rotators model for the description of internal dynamics. Analytical relationships between NMR order parameters and conformational entropies are derived, and the possibility to extract the latter from NMR experiments is discussed. These results are illustrated in the case of the calcium-binding protein calbindin. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
16. Local cooperativity in an amyloidogenic state of human lysozyme observed at atomic resolution
- Author
-
Dhulesia, Anne, Cremades, Nunilo, Kumita, Janet R., Shang-Te Danny Hsu, Mossuto, Maria F., Dumoulin, Mireille, Nietlispach, Daniel, Akke, Mikael, Salvatella, Xavier, and Dobson, Christopher M.
- Subjects
Calorimetry -- Usage ,Glycoproteins -- Structure ,Glycoproteins -- Chemical properties ,Nuclear magnetic resonance spectroscopy -- Usage ,Chemistry - Abstract
A range of biophysical techniques that includes differential scanning calorimetry and nuclear magnetic resonance spectroscopy are applied to characterize the structural and physicochemical properties and thermal unfolding of the amyloidogenic states of the protein. The overall results obtained provide a rational explanation for the atomic resolution of the initial events underlying amyloid formation by a globular protein.
- Published
- 2010
17. The Significance of the Location of Mutations for the Native-State Dynamics of Human Lysozyme
- Author
-
Minkoo, Ahn, Christine L, Hagan, Ana, Bernardo-Gancedo, Erwin, De Genst, Francisco N, Newby, John, Christodoulou, Anne, Dhulesia, Mireille, Dumoulin, Carol V, Robinson, Christopher M, Dobson, and Janet R, Kumita
- Subjects
Models, Molecular ,Amyloid ,Protein Domains ,Enzyme Stability ,Mutation ,Humans ,Proteins ,Muramidase ,Protein Multimerization ,Protein Structure, Secondary - Abstract
The conversion of human lysozyme into amyloid fibrils is associated with a rare but fatal hereditary form of nonneuropathic systemic amyloidosis. The accumulation of large amounts of aggregated protein is thought to be initiated by the formation of transient intermediate species of disease-related lysozyme variants, essentially due to the loss of global cooperativity under physiologically relevant conditions. Interestingly, all five naturally occurring, amyloidogenic, single-point mutations are located in the β-domain of lysozyme, the region that is predominantly unfolded during the formation of the transient intermediate species. Given the lack of known naturally occurring, amyloidogenic, single-point mutations in the α-domain, we chose three specific mutations to address the effects that location may have on native-state dynamics, as studied by hydrogen-deuterium (HD) exchange experiments analyzed by NMR spectroscopy, and mass spectrometry. We compared the effect of a destabilizing α-domain mutation (I23A) with that of the well-characterized I59T β-domain variant. We also investigated the effect of a mutation that has minor effects on native-state stability at the domain interface (I56V) and compared it with that of a variant with similar stability within the C-helix (I89V). We show that when variants have similar reduced native-state stabilities, the location of the mutation (I23A versus I59T) is crucial to the native-state dynamics, with the α-domain mutation having a significantly lower ability to populate transient intermediate species under physiologically relevant conditions. Interestingly, the mutation at the interface (I56V) has a greater effect in facilitating the formation of transient intermediate species at elevated temperatures compared with the variants containing α-domain mutations, even though this mutation results in only minor changes to the native-state stability of lysozyme. These findings reveal that the location of specific mutations is an important factor in determining the native-state dynamical properties of human lysozyme in the context of its propensity to populate the aggregation-prone transient intermediate species associated with pathogenic amyloid formation.
- Published
- 2016
18. Analyse der Energiebarrieren für das Wachstum von Amyloidfibrillen
- Author
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Christopher M. Dobson, Tuomas P. J. Knowles, Duncan A. White, Anne Dhulesia, Mark E. Welland, and Alexander K. Buell
- Subjects
Chemistry ,General Medicine - Published
- 2012
19. Mapping of two networks of residues that exhibit structural and dynamical changes upon binding in a PDZ domain protein
- Author
-
Dhulesia, Anne and Gsponer, Joerg
- Subjects
Phosphatases -- Chemical properties ,Protein binding -- Analysis ,Tyrosine -- Chemical properties ,Chemistry - Abstract
The changes in structure and dynamics occurring in the second PDZ domain of human tyrosine phosphatase 1E upon binding the small peptide RA-GEF2 are described. The analysis of the dynamical properties of the residues in these interconnected networks has disclosed conformational changes are transmitted through pathways of coupled side-chain reorientations.
- Published
- 2008
20. Local Cooperativity in an Amyloidogenic State of Human Lysozyme Observed at Atomic Resolution
- Author
-
Shang-Te Danny Hsu, Mikael Akke, Mireille Dumoulin, Nunilo Cremades, Anne Dhulesia, Daniel Nietlispach, Maria F. Mossuto, Janet R. Kumita, Xavier Salvatella, and Christopher M. Dobson
- Subjects
Models, Molecular ,Amyloid ,Protein Folding ,Magnetic Resonance Spectroscopy ,Globular protein ,Cooperativity ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Article ,Catalysis ,03 medical and health sciences ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,Differential scanning calorimetry ,Humans ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Chemistry ,Genetic Variation ,General Chemistry ,Nuclear magnetic resonance spectroscopy ,Hydrogen-Ion Concentration ,Protein tertiary structure ,0104 chemical sciences ,Crystallography ,Mutation ,Muramidase ,Protein folding ,Lysozyme - Abstract
The partial unfolding of human lysozyme underlies its conversion from the soluble state into amyloid fibrils observed in a fatal hereditary form of systemic amyloidosis. To understand the molecular origins of the disease, it is critical to characterize the structural and physicochemical properties of the amyloidogenic states of the protein. Here we provide a high-resolution view of the unfolding process at low pH for three different lysozyme variants, the wild-type protein and the mutants I56T and I59T, which show variable stabilities and propensities to aggregate in vitro. Using a range of biophysical techniques that includes differential scanning calorimetry and nuclear magnetic resonance spectroscopy, we demonstrate that thermal unfolding under amyloidogenic solution conditions involves a cooperative loss of native tertiary structure, followed by progressive unfolding of a compact, molten globule-like denatured state ensemble as the temperature is increased. The width of the temperature window over which the denatured ensemble progressively unfolds correlates with the relative amyloidogenicity and stability of these variants, and the region of lysozyme that unfolds first maps to that which forms the core of the amyloid fibrils formed under similar conditions. Together, these results present a coherent picture at atomic resolution of the initial events underlying amyloid formation by a globular protein.
- Published
- 2010
21. Inhibition of α-Synuclein Fibril Elongation by Hsp70 Is Governed by a Kinetic Binding Competition between α-Synuclein Species
- Author
-
Aprile, Francesco A., primary, Arosio, Paolo, additional, Fusco, Giuliana, additional, Chen, Serene W., additional, Kumita, Janet R., additional, Dhulesia, Anne, additional, Tortora, Paolo, additional, Knowles, Tuomas P. J., additional, Vendruscolo, Michele, additional, Dobson, Christopher M., additional, and Cremades, Nunilo, additional
- Published
- 2017
- Full Text
- View/download PDF
22. Author response: Structure of a low-population intermediate state in the release of an enzyme product
- Author
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Alfonso De Simone, Francesco A. Aprile, Michele Vendruscolo, Christopher M. Dobson, and Anne Dhulesia
- Subjects
chemistry.chemical_classification ,education.field_of_study ,Enzyme ,Stereochemistry ,Chemistry ,Product (mathematics) ,Population ,Structure (category theory) ,Intermediate state ,education - Published
- 2014
23. Experimental free energy surfaces reveal the mechanisms of maintenance of protein solubility
- Author
-
Alfonso De Simone, Christopher M. Dobson, Anne Dhulesia, Fabrizio Chiti, Michele Vendruscolo, Gemma Soldi, Shang-Te Danny Hsu, De Simone, A., Dhulesia, A., Soldi, G., Vendruscolo, M., Hsu, S. -T. D., Chiti, F., and Dobson, C. M.
- Subjects
Models, Molecular ,Magnetic Resonance Spectroscopy ,Multidisciplinary ,Protein Conformation ,Chemistry ,Avoidance of protein aggregation ,Sequence (biology) ,Nuclear magnetic resonance spectroscopy ,Molecular Dynamics Simulation ,Biological Sciences ,Acylphosphatase ,Acid Anhydride Hydrolases ,Folding (chemistry) ,Molecular dynamics ,Drosophila melanogaster ,Protein structure ,Solubility ,Biochemistry ,Molecular simulation ,Biophysics ,Native state ,Animals ,Free energy barrier ,Protein misfolding - Abstract
The identification of the factors that enable normally folded proteins to remain in their soluble and functional states is crucial for a comprehensive understanding of any biological system. We have determined a series of energy landscapes of the acylphosphatase from Drosophila melanogaster under a variety of conditions by combining NMR measurements with restrained molecular dynamics simulations. We thus analyzed the differences in the structures, dynamics, and energy surfaces of the protein in its soluble state or in situations where it aggregates through conformational states that have native-like structure, folding stability, and enzymatic activity. The study identifies the nature of the energy barriers that under normal physiological conditions prevent the protein ensemble from populating dangerous aggregation-prone states. We found that such states, although similar to the native conformation, have altered surface charge distribution, alternative topologies of the β-sheet region, and modified solvent exposure of hydrophobic surfaces and aggregation-prone regions of the sequence. The identified barriers allow the protein to undergo functional dynamics while remaining soluble and without a significant risk of misfolding and aggregation into nonfunctional and potentially toxic species.
- Published
- 2011
24. Detailed analysis of the energy barriers for amyloid fibril growth
- Author
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Mark E. Welland, Tuomas P. J. Knowles, Anne Dhulesia, Christopher M. Dobson, Duncan A. White, and Alexander K. Buell
- Subjects
Arrhenius equation ,Amyloid ,Chemistry ,Nucleation ,General Chemistry ,Quartz crystal microbalance ,Fibril ,Microscopy, Atomic Force ,Catalysis ,Arrhenius plot ,Crystallography ,symbols.namesake ,Kinetics ,Solubility ,Biophysics ,symbols ,Protein folding ,Elongation - Abstract
Solubility is a key requirement for the functioning of a protein within the complex network of cellular components. A class of highly debilitating disorders, including Alzheimer s and Parkinson s diseases, is related to the loss of solubility of peptides and proteins that is accompanied by their aggregation into ordered amyloid fibrils. It has been found that, under at least some physiological conditions, these aggregates are thermodynamically more stable than the native forms of biological polypeptides. This finding raises questions as to the factors governing the crucial ability of native proteins to remain soluble even under conditions where they do not necessarily correspond to global minima on free energy landscapes. In order to address this question, we have studied in detail the kinetics of elongation of amyloid fibrils formed by a wide range of polypeptides. The formation of amyloid fibrils from soluble protein molecules involves at least a primary nucleation step, an elongation step and, in general, a secondary nucleation process such as fibril fragmentation. In addition, multiple interconverting oligomeric intermediates can be involved. Measurements of amyloid growth in bulk solution often reflect all of these processes, and it can therefore be extremely challenging to determine accurately the concentrations of the different species and the rate constants for the individual elementary steps. In order to overcome these difficulties, surface-based sensing techniques, notably those based on quartz crystal microbalance (QCM) measurements, have been developed in recent years, by which the growth of a constant, surfacebound ensemble of fibrils can be monitored. These methods make use of the fact that in the presence of preexisting fibrils, aggregation can be highly accelerated through seeding. This seeding process corresponds to the elongation of existing fibrils and can be well described as diffusional motion over a single free energy barrier, involving no intermediate species between monomeric and fibrillar peptide. The elongation of the fibrils is monitored through the increase in hydrodynamic mass bound to the quartz crystal, as the rate of change of the resonant frequency is proportional to the average elongation rate of the fibrils. The opportunity to image the sensor surface enables an estimation of the surface density of fibrils, an important factor in the determination of the rate constants in this bimolecular reaction, the overall rate of which depends on both the concentration of soluble protein and the number of available fibril ends. In addition, the lengths of the fibrils before and after an experiment can be compared and therefore an independent measurement of the length increase can be made and used to calibrate the frequency response of the microbalance. The covalent irreversible attachment of the preformed fibrils to the sensor surface and the subsequent passivation of the remaining surface, as well as the short duration of individual experiments, ensure that only fibril elongation is measured, and that primary and secondary nucleation events can be neglected; this selectivity is confirmed by the high reproducibility of the data obtained from QCM measurements. The starting point of a systematic study of the energy barriers that separate the soluble from the fibrillar states of a protein is the measurement of the temperature dependence of the fibril elongation rate; such an approach allows for the determination of the enthalpy of activation from an Arrhenius plot. The temperature dependence of amyloid growth has already been measured for a range of amyloidogenic peptides and proteins, and where possible these literature data are included in the analysis described herein. These published data have been acquired with a range of different techniques, mainly involving small-molecule labels such as Thioflavin-T. In such experiments, the exclusive study of the elementary elongation reaction is challenging and therefore the published values on energy barriers may in some cases refer to a combination of different elementary steps. We have, however, used the QCM approach, which is particularly suited for such measurements, to increase substantially the size of the available dataset by studying peptides and proteins of very diverse sequence that form amyloid fibrils under varied solution conditions. Figure 1 shows, as an example, raw QCM data for the temperature dependence of PI3K-SH3 amyloid fibril elongation, as well as AFM images of the QCM sensor surface. Similar experiments were performed for a range of other peptides and proteins, and the resulting Arrhenius plots are shown in Figure 2. No pronounced curvature is apparent, unlike that sometimes observed for protein folding; this [*] A. K. Buell, M. E. Welland Nanoscience Centre, University of Cambridge 11 JJ Thomson Avenue, West Cambridge CB3 0FF (UK) E-mail: mew10@cam.ac.uk
- Published
- 2011
25. A non-natural variant of human lysozyme (I59T) mimics the in vitro behaviour of the I56T variant that is responsible for a form of familial amyloidosis
- Author
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Anne Dhulesia, Erwin De Genst, Christopher M. Dobson, Russell J.K. Johnson, Christine L. Hagan, Carol V. Robinson, Janet R. Kumita, Janice Dumont, John Christodoulou, and Mireille Dumoulin
- Subjects
Models, Molecular ,Amyloid ,Bioengineering ,Cooperativity ,010402 general chemistry ,Fibril ,01 natural sciences ,Biochemistry ,03 medical and health sciences ,Amyloid disease ,chemistry.chemical_compound ,medicine ,Humans ,Point Mutation ,Nuclear Magnetic Resonance, Biomolecular ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,Transition (genetics) ,Chemistry ,Amyloidosis ,Point mutation ,Deuterium Exchange Measurement ,Original Articles ,medicine.disease ,0104 chemical sciences ,Thermodynamics ,Muramidase ,Lysozyme ,Amyloidosis, Familial ,Biotechnology - Abstract
We report here the detailed characterisation of a non-naturally occurring variant of human lysozyme, I59T, which possesses a destabilising point mutation at the interface of the alpha- and beta-domains. Although more stable in its native structure than the naturally occurring variants that give rise to a familial form of systemic amyloidosis, I59T possesses many attributes that are similar to these disease-associated species. In particular, under physiologically relevant conditions, I59T populates transiently an intermediate in which a region of the structure unfolds cooperatively; this loss of global cooperativity has been suggested to be a critical feature underlying the amyloidogenic nature of the disease-associated lysozyme variants. In the present study, we have utilised this variant to provide direct evidence for the generic nature of the conformational transition that precedes the ready formation of the fibrils responsible for lysozyme-associated amyloid disease. This non-natural variant can be expressed at higher levels than the natural amyloidogenic variants, enabling, for example, singly isotopically labelled protein to be generated much more easily for detailed structural studies by multidimensional NMR spectroscopy. Moreover, we demonstrate that the I59T variant can readily form fibrils in vitro, similar in nature to those of the amyloidogenic I56T variant, under significantly milder conditions than are needed for the wild-type protein.
- Published
- 2010
26. The non-core regions of human lysozyme amyloid fibrils influence cytotoxicity
- Author
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Christopher M. Dobson, Anne Dhulesia, Angelo Fontana, Glyn L. Devlin, Xavier Salvatella, Erica Frare, Patrizia Polverino de Laureto, Mireille Dumoulin, Maria F. Mossuto, and Janet R. Kumita
- Subjects
Amyloid ,Spectrophotometry, Infrared ,Cell Survival ,human lysozyme ,Tetrazolium Salts ,Protein aggregation ,DMSO, dimethyl sulfoxide ,010402 general chemistry ,Fibril ,01 natural sciences ,DTNB, 5,5′-dithiobis-(2-nitrobenzoic acid) ,Article ,Cell Line ,ANS, 1-anilino-naphthalene-8-sulfonic acid ,polymorphism ,03 medical and health sciences ,chemistry.chemical_compound ,MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide ,amyloid fibrils ,Microscopy, Electron, Transmission ,IR, infrared ,Structural Biology ,ThT, thioflavin T ,Humans ,Viability assay ,TCEP, tris(carboxyethyl)phosphine ,Cytotoxicity ,TEM, transmission electron microscopy ,Molecular Biology ,030304 developmental biology ,GdnSCN, guanidine thiocyanate ,Neurons ,0303 health sciences ,Chemistry ,Depolymerization ,Protein Stability ,toxicity ,stability ,In vitro ,0104 chemical sciences ,GdnHCl, guanidine hydrochloride ,Thiazoles ,Biochemistry ,ATR-FTIR, attenuated total reflectance Fourier transform infrared ,TCEP ,Muramidase ,Lysozyme - Abstract
Identifying the cause of the cytotoxicity of species populated during amyloid formation is crucial to understand the molecular basis of protein deposition diseases. We have examined different types of aggregates formed by lysozyme, a protein found as fibrillar deposits in patients with familial systemic amyloidosis, by infrared spectroscopy, transmission electron microscopy, and depolymerization experiments, and analyzed how they affect cell viability. We have characterized two types of human lysozyme amyloid structures formed in vitro that differ in morphology, molecular structure, stability, and size of the cross-β core. Of particular interest is that the fibrils with a smaller core generate a significant cytotoxic effect. These findings indicate that protein aggregation can give rise to species with different degree of cytotoxicity due to intrinsic differences in their physicochemical properties.
- Published
- 2010
27. Structure of a low-population intermediate state in the release of an enzyme product
- Author
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De Simone, Alfonso, primary, Aprile, Francesco A, additional, Dhulesia, Anne, additional, Dobson, Christopher M, additional, and Vendruscolo, Michele, additional
- Published
- 2015
- Full Text
- View/download PDF
28. The Non-core Regions of Human Lysozyme Amyloid Fibrils Give Rise to Cytotoxicity
- Author
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Mossuto, Mf, Dhulesia, A, Devlin, G, Frare, Erica, Kumita, Jr, POLVERINO DE LAURETO, Patrizia, Dumoulin, M, Fontana, Angelo, Dobson, Cm, and Salvatella, X.
- Subjects
amyloid fibrils ,human lysozyme, amyloid fibrils, polymorphism, stability, toxicity ,human lysozyme ,toxicity ,stability ,polymorphism - Published
- 2010
29. Author response: Structure of a low-population intermediate state in the release of an enzyme product
- Author
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De Simone, Alfonso, primary, Aprile, Francesco A, additional, Dhulesia, Anne, additional, Dobson, Christopher M, additional, and Vendruscolo, Michele, additional
- Published
- 2014
- Full Text
- View/download PDF
30. BIOT 243-Biophysical study of the aggregation of human lysozyme into amyloid fibrils
- Author
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Dhulesia, A, Baldwin, A, Mossuto, M, Salvatella, X, and Dobson, C
- Published
- 2008
31. Mapping of two networks of residues that exhibit structural and dynamical changes upon binding in a PDZ domain protein
- Author
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Joerg Gsponer, Anne Dhulesia, and Michele Vendruscolo
- Subjects
Models, Molecular ,Protein Conformation ,PDZ domain ,Protein Tyrosine Phosphatase, Non-Receptor Type 13 ,PDZ Domains ,Decreased mobility ,Protein tyrosine phosphatase ,Biochemistry ,Peptide Mapping ,Catalysis ,Molecular dynamics ,Colloid and Surface Chemistry ,Small peptide ,Cluster Analysis ,Humans ,skin and connective tissue diseases ,Nuclear Magnetic Resonance, Biomolecular ,Binding Sites ,Chemistry ,General Chemistry ,Nmr data ,Crystallography ,Models, Chemical ,Biophysics ,Thermodynamics ,sense organs ,Binding domain - Abstract
We describe the changes in structure and dynamics that occur in the second PDZ domain of human tyrosine phosphatase 1E upon binding the small peptide RA-GEF2 by an analysis of NMR data based on their use as ensemble-averaged restraints in molecular dynamics simulations. This approach reveals the presence of two interconnected networks of residues, the first exhibiting structural changes and the second dynamical changes upon binding, and it provides a detailed mapping of the regions of increased and decreased mobility upon binding. Analysis of the dynamical properties of the residues in these networks reveals that conformational changes are transmitted through pathways of coupled side-chain reorientations. These results illustrate how the strategy we described, in which NMR data are used in combination with molecular dynamics simulations, can be used to characterize in detail the complex organization of the changes in structure and dynamics that take place in proteins upon binding.
- Published
- 2008
32. Networks of coupled rotators: Relationship between structures and internal dynamics in metal-binding proteins
- Author
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Dhulesia, Anne, Geoffrey, Bodenhausen, Abergel, Daniel, Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), and Perron, Nicolas
- Subjects
[CHIM.ORGA]Chemical Sciences/Organic chemistry ,[CHIM.ORGA] Chemical Sciences/Organic chemistry ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience
- Published
- 2008
33. Networks of coupled rotators: relationship between structures and internal dynamics in metal-binding proteins. Applications to apo- and holo-calbindin
- Author
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Daniel Abergel, Anne Dhulesia, and Geoffrey Bodenhausen
- Subjects
0303 health sciences ,Calbindins ,Chemistry ,Protein Conformation ,education ,Dynamics (mechanics) ,Metal binding proteins ,General Chemistry ,010402 general chemistry ,Crystallography, X-Ray ,01 natural sciences ,Biochemistry ,Calbindin ,Catalysis ,0104 chemical sciences ,03 medical and health sciences ,Crystallography ,Colloid and Surface Chemistry ,S100 Calcium Binding Protein G ,Chemical physics ,Metalloproteins ,Animals ,Humans ,030304 developmental biology - Abstract
This article presents an analysis of the internal dynamics of the Ca2+-binding protein calbindin, based on the Networks of Coupled Rotators (NCRs) introduced recently. Several fundamental and practical issues raised by this approach are investigated. The roles of various parameters of the model are examined. The NCR model is shown to account for the modifications of the internal dynamics upon Ca2+ binding by calbindin. Two alternative strategies to estimate local internal effective correlation times of the protein are proposed, which offer good agreement between predictions and experiment.
- Published
- 2007
34. Hsp70 Oligomerization Is Mediated by an Interaction between the Interdomain Linker and the Substrate-Binding Domain
- Author
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Aprile, Francesco A., primary, Dhulesia, Anne, additional, Stengel, Florian, additional, Roodveldt, Cintia, additional, Benesch, Justin L. P., additional, Tortora, Paolo, additional, Robinson, Carol V., additional, Salvatella, Xavier, additional, Dobson, Christopher M., additional, and Cremades, Nunilo, additional
- Published
- 2013
- Full Text
- View/download PDF
35. Performances of Transient Two-Phase Flow Models
- Author
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D. Lopez, H. Dhulesia, E. Leporcher, and P. Duchet-Suchaux
- Abstract
Abstract When a process engineer is asked to design transportation and treatment facilities or to recommend operating procedures, he needs to run steady state and transient multiphase flow computer programs. The predictions regarding steady state two-phase flows of the mechanistic models OLGA, TACITE and TUFFP have been assessed in a previous SPE paper (ref. 1). As a logical continuation, the performances of these models regarding transient two-phase flows are compared in this paper first on transient loop data and then on field data. The main features of each model are presented as well. From the analysis of the features and the performances of the three codes, some guidelines to improve each model are indicated. Introduction Formerly, people used to run steady state empirical correlations for the design of multiphase production system including well, pipeline and downstream facilities. But it appeared very quickly that such correlations could be used only in the case of wells or pipelines similar to the ones the correlations were derived from (same diameter, same profile and same fluids). Since the early 1980's, with the coming of a number of mechanistic models onto the market (PEPITE, WELLSIM, OLGA, TUFFP), people know that it is less risky to use steady state mechanistic models to design the multiphase production systems. Given the inlet and the outlet pressures as well as the gas and liquid flow rates, these steady state models are reliable enough to figure out the right diameter. But when it comes to designing facilities downstream of a pipeline in which flow rates can change fast, these models often prove inadequate. They are incapable of even predicting the flow rates at the pipeline outlet when the inlet flow rates are low enough to give rise to such well-known phenomena as terrain slugging or severe slugging. The only way to deal with these highly varying outlet flow rates and consequently to design properly the facilities downstream of the pipeline is to use transient flow simulation models. Among such models we have tested OLGA, TUFFP and TACITE. The three programs were compared first against loop data and next against field data. The advantage of data measured on a loop is that the fluid properties and the flow rates are known precisely. If discrepancies exist between the measures and the predictions, only the hydrodynamic model can be called into question. For the code developers, this is a first step needed to establish confidence before pursuing with the comparison against field data. Such a comparison is required by any potential user of a model to get him to trust the program in his turn. Data from the loop set-up within the frame of the Tulsa University Fluid Flow Project were used for the comparison. This loop will be briefly described here-after. Specific measurement campaigns were conducted on a number of real pipelines operated by Elf Exploration Production and Total to acquire relevant transient flow data necessary to test any transient flow simulation program. Among them, we have selected one pipeline with very severe changes in the inlet flow rates. As expected, none of the three programs can predict perfectly all the transient flow conditions. From the analysis of the main features of the models on the one hand and from the analysis of the conditions where the discrepancies are the largest on the other hand, the authors will try to make clear some areas where improvements are needed. Data description Loop data. The data have been acquired on the test loop set up in the frame of the Tulsa University Fluid Flow Project (TUFFP). The test facility (fig. 1) is described by Minami (ref. 2). It is a 420 m long, 77.9 mm diameter horizontal steel pipeline that uses air and kerosene as working fluids. It is operated at atmospheric pressure. P. 631^
- Published
- 1997
36. Critical Evaluation of Mechanistic Two-Phase Flow Pipeline and Well Simulation Models
- Author
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D. Lopez and H. Dhulesia
- Subjects
Pipeline transport ,Pressure drop ,Engineering ,Software ,Closure (computer programming) ,business.industry ,Simulation modeling ,Point (geometry) ,Two-phase flow ,business ,Pipeline (software) ,Algorithm - Abstract
Abstract Mechanistic steady state simulation models, rather than empirical correlations, are used for a design of multiphase production system including well, pipeline and downstream installations. Among the available models, PEPITE, WELLSIM, OLGA, TACITE and TUFFP are widely used for this purpose and consequently, a critical evaluation of these models is needed. An extensive validation methodology is proposed which consists of two distinct steps : first to validate the hydrodynamic point model using the test loop data and, then to validate the over-all simulation model using the real pipelines and wells data. The test loop databank used in this analysis contains about 5952 data sets originated from four different test loops and a majority of these data are obtained at high pressures (up to 90 bars) with real hydrocarbon fluids. Before performing the model evaluation, physical analysis of the test loops data is required to eliminate non-coherent data. The evaluation of these point models demonstrates that the TACITE and OLGA models can be applied to any configuration of pipes. The TACITE model performs better than the OLGA model because it uses the most appropriate closure laws from the literature validated on a large number of data. The comparison of predicted and measured pressure drop for various real pipelines and wells demonstrates that the TACITE model is a reliable tool. Introduction Nowadays, the multiphase production technique has become a standard method for the development of marginal fields due to significant reduction in CAPEX and OPEX compared to those obtained in the conventional production method. The multiphase production technology consists in the transport of untreated wellhead effluent through a single pipeline either to an existing processing platform or to on-shore processing facilities. In the beginning of the production, the wellhead pressure can be sufficient, depending on the transportation distance, to achieve transportation up to the treatment installations. If the wellhead pressure is not sufficient, multiphase pumps can be used to boost the inlet pressure. The correct predictions of pressure drop, liquid hold-up and flow regime are vital to design a multiphase transport system i.e. pipeline, multiphase pump and downstream process facilities. The old approach to design a multiphase pipeline was to use empirical correlations developed from the test loop experimental data. Nowadays, these correlations are hardly used as they do not take the physical phenomena into consideration and the accuracy of their predictions can be very poor. Since the mid 1970's, significant progress has been made to understand the physics of two-phase flow in pipes and wells. This progress has resulted in several two-phase flow mechanistic models to simulate the pipelines and wells under steady state as well as transient conditions. The use of these steady state mechanistic models allows to correctly predict the pressure drop, liquid hold-up and flow regime for a pipeline and well operating under any condition. The main purpose of this paper is first to define a proper methodology to carry out the validation of a mechanistic two-phase flow pipeline and well simulation model. Then, in accordance with the established methodology, a critical evaluation of the existing pipeline and well simulation models has been carried out using a large number of test loop, real pipeline and well data. This study identifies the domain of application, limitations and weaknesses of each model. Brief description of different mechanistic models As mentioned earlier, most oil companies use mechanistic models rather than empirical correlations to simulate two-phase flow pipelines and wells. Several mechanistic models exist, but only the following models have been investigated in this paper either because they are commercially available or reputed as being good tools:–PEPITE–WELLSIM P. 393
- Published
- 1996
37. Analyse der Energiebarrieren für das Wachstum von Amyloidfibrillen
- Author
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Buell, Alexander K., primary, Dhulesia, Anne, additional, White, Duncan A., additional, Knowles, Tuomas P. J., additional, Dobson, Christopher M., additional, and Welland, Mark E., additional
- Published
- 2012
- Full Text
- View/download PDF
38. Detailed Analysis of the Energy Barriers for Amyloid Fibril Growth
- Author
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Buell, Alexander K., primary, Dhulesia, Anne, additional, White, Duncan A., additional, Knowles, Tuomas P. J., additional, Dobson, Christopher M., additional, and Welland, Mark E., additional
- Published
- 2012
- Full Text
- View/download PDF
39. Disulfide Bonds Reduce the Toxicity of the Amyloid Fibrils Formed by an Extracellular Protein
- Author
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Mossuto, Maria F., primary, Bolognesi, Benedetta, additional, Guixer, Bernat, additional, Dhulesia, Anne, additional, Agostini, Federico, additional, Kumita, Janet R., additional, Tartaglia, Gian G., additional, Dumoulin, Mireille, additional, Dobson, Christopher M., additional, and Salvatella, Xavier, additional
- Published
- 2011
- Full Text
- View/download PDF
40. Population of Nonnative States of Lysozyme Variants Drives Amyloid Fibril Formation
- Author
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Buell, Alexander K., primary, Dhulesia, Anne, additional, Mossuto, Maria F., additional, Cremades, Nunilo, additional, Kumita, Janet R., additional, Dumoulin, Mireille, additional, Welland, Mark E., additional, Knowles, Tuomas P. J., additional, Salvatella, Xavier, additional, and Dobson, Christopher M., additional
- Published
- 2011
- Full Text
- View/download PDF
41. TACITE: A Transient Tool for Multiphase Pipeline and Well Simulation
- Author
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C.L. Pauchon and Hasmuekh Dhulesia
- Subjects
Petroleum engineering ,Pipeline (computing) ,Transient (oscillation) ,Geology - Published
- 1994
42. The Non-Core Regions of Human Lysozyme Amyloid Fibrils Influence Cytotoxicity
- Author
-
Mossuto, Maria F., primary, Dhulesia, Anne, additional, Devlin, Glyn, additional, Frare, Erica, additional, Kumita, Janet R., additional, de Laureto, Patrizia Polverino, additional, Dumoulin, Mireille, additional, Fontana, Angelo, additional, Dobson, Christopher M., additional, and Salvatella, Xavier, additional
- Published
- 2010
- Full Text
- View/download PDF
43. Performances of Transient Two-Phase Flow Models
- Author
-
Lopez, D., additional, Dhulesia, H., additional, Leporcher, E., additional, and Duchet-Suchaux, P., additional
- Published
- 1997
- Full Text
- View/download PDF
44. Performances of Transient Two-Phase Flow Models
- Author
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Lopez, D., primary, Dhulesia, H., additional, Leporcher, E., additional, and Duchet-Suchaux, P., additional
- Published
- 1997
- Full Text
- View/download PDF
45. Field Installation of an Acoustic Slug-Detection System
- Author
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Dhulesia, Hasmukh, primary, Bernicot, Michel, additional, and Romanet, Thierry, additional
- Published
- 1997
- Full Text
- View/download PDF
46. Critical Evaluation of Mechanistic Two-Phase Flow Pipeline and Well Simulation Models
- Author
-
Dhulesia, H., additional and Lopez, D., additional
- Published
- 1996
- Full Text
- View/download PDF
47. TACITE: A Transient Tool for Multiphase Pipeline and Well Simulation
- Author
-
Pauchon, C.L., primary and Dhulesia, Hasmuekh, additional
- Published
- 1994
- Full Text
- View/download PDF
48. Prediction of the effect of weeping on distillation tray efficiency.
- Author
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Lockett, M. J., Rahman, M. A., and Dhulesia, H. A.
- Published
- 1984
- Full Text
- View/download PDF
49. Prediction of the effect of weeping on distillation tray efficiency
- Author
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M.J. Lockett, M. A. Rahman, and H.A. Dhulesia
- Subjects
Engineering drawing ,Environmental Engineering ,Tray ,Plug flow ,law ,Chemistry ,General Chemical Engineering ,Analytical equations ,Mechanics ,Distillation ,Biotechnology ,law.invention - Abstract
The reduction in distillation tray efficiency caused by uniform weeping of liquid from the tray has been calculated. Numerical results are presented for all three Lewis cases over the range of variables of interest to tray designers. Analytical equations are given for Lewis' cases 2 and 3 for plug flow of liquid on the tray.
- Published
- 1984
50. Murphree Plate Efficiency with Nonuniform Vapour Distribution
- Author
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M.M. Lockett and H.A. Dhulesia
- Subjects
inorganic chemicals ,Materials science ,technology, industry, and agriculture ,General Engineering ,Péclet number ,Mechanics ,Eddy diffusion ,Hydraulic head ,symbols.namesake ,Distribution (mathematics) ,Control theory ,biological sciences ,health occupations ,symbols ,bacteria ,Liquid flow ,Reduction (mathematics) - Abstract
The eddy diffusion model is used to predict the relationship between point efficiency and Murphree plate efficiency, where, because of the hydraulic gradient, the vapour is distributed nonuniformly as it passes through the plate. The vapour is assumed to be unmixed between plates, and liquid flow in the same direction and opposite directions on successive plates is considered. The results show that a decrease of plate efficiency is obtained with nonuniform vapour distribution compared with that obtained with uniformly distributed vapour. The effect of nonuniform vapour distribution is greatest for plates having a liquid Peclet number of about 5. For most plates, operating under normal conditions, the reduction in efficiency is small.
- Published
- 1980
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