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Journal articleFurse S, Brooks NJ, Seddon AM, et al., 2012,
Lipid membrane curvature induced by distearoyl phosphatidylinositol 4-phosphate
, Soft Matter -
Journal articleDickson CJ, Rosso L, Betz RM, et al., 2012,
GAFFlipid: a General Amber Force Field for the accurate molecular dynamics simulation of phospholipid
, Soft Matter, Vol: 8, Pages: 9617-9627-9617-9627Previous attempts to simulate phospholipid bilayers using the General Amber Force Field (GAFF) yielded many bilayer characteristics in agreement with experiment, however when using a tensionless NPT ensemble the bilayer is seen to compress to an undesirable extent resulting in low areas per lipid and high order parameters in comparison to experiment. In this work, the GAFF Lennard-Jones parameters for the simulation of acyl chains are corrected to allow the accurate and stable simulation of pure lipid bilayers. Lipid bilayers comprised of six phospholipid types were simulated for timescales approaching a quarter of a microsecond under tensionless constant pressure conditions using Graphics Processing Units. Structural properties including area per lipid, volume per lipid, bilayer thickness, order parameter and headgroup hydration show favourable agreement with available experimental values. Expanding the system size from 72 to 288 lipids and a more experimentally realistic 2 [times] 288 lipid bilayer stack induces little change in the observed properties. This preliminary work is intended for combination with the new AMBER Lipid11 modular force field as part of on-going attempts to create a modular phospholipid AMBER force field allowing tensionless NPT simulations of complex lipid bilayers.
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Journal articleMak LH, Georgiades SN, Rosivatz E, et al., 2011,
A Small Molecule Mimicking a Phosphatidylinositol (4,5)-Bisphosphate Binding Pleckstrin Homology Domain
, ACS Chemical Biology, ISSN: 1554-8929 -
Conference paperAlibhai D, Kumar S, Kelly D, et al., 2011,
An automated wide-field, time-gated, optically sectioning, fluorescence lifetime imaging multiwell plate reader for high-content analysis of protein-protein interactions
, Conference on Three-Dimensional and Multidimensional Microscopy - Image Acquisition and Processing XVIII, Publisher: SPIE-INT SOC OPTICAL ENGINEERING, ISSN: 0277-786X -
Journal articleSmith MEB, Gunn RM, Rosivatz E, et al., 2010,
Development of chemical probes: Toward the mode of action of a methylene-linked di(aryl acetate) E1
, Bioorganic & Medicinal Chemistry, Vol: 18, Pages: 4917-4927, ISSN: 0968-0896 -
Journal articleHo KK, Rosivatz E, Gunn RM, et al., 2009,
The novel molecule 2-[5-(2-chloroethyl)-2-acetoxy-benzyl]-4-(2-chloroethyl)-phenyl acetate inhibits phosphoinositide 3-kinase/Akt/mammalian target of rapamycin signalling through JNK activation in cancer cells
, FEBS J., Vol: 276, Pages: 4037-4050Screening a compound library of compound 48/80 analogues, we identified 2-[5-(2-chloroethyl)-2-acetoxy-benzyl]-4-(2-chloroethyl)-phenyl acetate (E1) as a novel inhibitor of the phosphoinositide 3-kinase/Akt pathway. In order to determine the mechanism of action of E1, we analysed the effect of E1 on components of the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway. E1 demonstrated dose-dependent and time-dependent repression of Akt and mTOR activity in prostate and breast cancer cell lines, PC-3 and MCF-7, respectively. Inhibition of Akt and mTOR activity by E1 also coincided with increased c-Jun NH2-terminal kinase (JNK) phosphorylation. However, the mode of action of E1 is different from that of the mTOR inhibitor rapamycin. Proliferation and cell cycle analysis revealed that E1 induced cell cycle arrest and cell death in PC-3 and MCF-7 cells. Moreover, pretreatment of cancer cells with the JNK inhibitor SP600125 abolished the repression of Akt and mTOR activity by E1, indicating that the inhibition of Akt and mTOR by E1 is mediated through JNK activation. Consistently, E1 repressed Akt and mTOR activity in wild-type and p38-null mouse embryonic fibroblasts (MEFs), but not in MEFs lacking JNK1/2, and JNK-null MEFs were less sensitive to the antiproliferative effects of E1. We further showed that E1 can function cooperatively with suboptimal concentrations of paclitaxel to induce cell death in PC-3 and MCF-7 cells. Taken together, these data suggest that E1 induces cancer cell death through the JNK-dependent repression of Akt and mTOR activity and may provide a valuable compound for further development and research
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Journal articleMulet X, Rosivatz E, Ho KK, et al., 2009,
Spatial localization of PtdInsP2 in phase-separated giant unilamellar vesicles with a fluorescent PLC-delta 1 PH domain
, Methods Mol.Biol., Vol: 462, Pages: 135-144This chapter describes a method for the preparation of giant unilamellar vesicles containing phosphatidylinositol 4,5-bisphosphate that are larger than 20 microm in size. The phospholipids composition of the vesicular membrane is such that fluid lamellar and liquid-ordered or gel phases are formed and separate within the confines of one vesicle. It outlines the preparation of a protein fluorescent label, pleckstrin homology domain from phospholipase C-delta 1, that binds specifically to phosphatidylinositol 4,5-bisphosphate. Using fluorescence microscopy, the presence and spatial position of this phosphorylated phosphatidylinositol lipid on the lipid membrane have been located with the pleckstrin homology domain. We show that phosphatidylinositol 4,5-bisphosphate and the phospholipase C-delta 1 pleckstrin homology domain are located to the fluid phase of the vesicle membrane. This approach can therefore show how membrane physical properties can affect enzyme binding to phosphatidylinositol 4,5-bisphosphate and thus further the understanding of important membrane processes such as endocytosis
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Journal articleMulet X, Templer RH, Woscholski R, et al., 2008,
Evidence that phosphatidylinositol promotes curved membrane interfaces
, LANGMUIR, Vol: 24, Pages: 8443-8447, ISSN: 0743-7463- Author Web Link
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- Citations: 31
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Journal articleBusch GK, Tate EW, Gaffney PR, et al., 2008,
Specific N-terminal protein labelling: use of FMDV 3C pro protease and native chemical ligation
, Chem.Commun.(Camb.), Pages: 3369-3371We report an effective strategy for generating N-terminal cysteinyl proteins by proteolytic cleavage using the enzyme 3C pro, suitable for a wide range of applications via native chemical ligation
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Conference paperOwen DM, Manning HB, de Beule P, et al., 2007,
Development of a hyperspectral fluorescence lifetime imaging microscope and its application to tissue imaging
, Conference on Imaging, Manipulation, and Analysis of Biomolecules, Cells, and Tissues V, Publisher: SPIE-INT SOC OPTICAL ENGINEERING, ISSN: 0277-786X- Author Web Link
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- Citations: 2
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