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https://www.readbyqxmd.com/read/28319451/a-best-example-of-channel-structure-annotation-by-molecular-simulation
#1
Shanlin Rao, Gianni Klesse, Phillip J Stansfeld, Stephen J Tucker, Mark S P Sansom
An increasing number of ion channel structures are being determined. This generates a need for computational tools to enable functional annotation of channel structures. However, a number of studies of ion channel and model pores have indicated that the physical dimensions of a pore are not always a reliable indicator of its conductive status. This is due to the unusual behavior of water within nano-confined spaces, resulting in a phenomenon referred to as 'hydrophobic gating'. We have recently demonstrated how simulating the behavior of water within an ion channel pore can be used to predict its conductive status...
March 20, 2017: Channels
https://www.readbyqxmd.com/read/28317903/stability-and-dynamics-of-membrane-spanning-dna-nanopores
#2
Vishal Maingi, Jonathan R Burns, Jaakko J Uusitalo, Stefan Howorka, Siewert J Marrink, Mark S P Sansom
Recently developed DNA-based analogues of membrane proteins have advanced synthetic biology. A fundamental question is how hydrophilic nanostructures reside in the hydrophobic environment of the membrane. Here, we use multiscale molecular dynamics (MD) simulations to explore the structure, stability and dynamics of an archetypical DNA nanotube inserted via a ring of membrane anchors into a phospholipid bilayer. Coarse-grained MD reveals that the lipids reorganize locally to interact closely with the membrane-spanning section of the DNA tube...
March 20, 2017: Nature Communications
https://www.readbyqxmd.com/read/28165704/biomimetic-phospholipid-membrane-organization-on-graphene-and-graphene-oxide-surfaces-a-molecular-dynamics-simulation-study
#3
Nathalie Willems, Ainhoa Urtizberea, Andrea F Verre, Maria Iliut, Mickael Lelimousin, Michael Hirtz, Aravind Vijayaraghavan, Mark S P Sansom
Supported phospholipid membrane patches stabilized on graphene surfaces have shown potential in sensor device functionalization, including biosensors and biocatalysis. Lipid dip-pen nanolithography (L-DPN) is a method useful in generating supported membrane structures that maintain lipid functionality, such as exhibiting specific interactions with protein molecules. Here, we have integrated L-DPN, atomic force microscopy, and coarse-grained molecular dynamics simulation methods to characterize the molecular properties of supported lipid membranes (SLMs) on graphene and graphene oxide supports...
February 28, 2017: ACS Nano
https://www.readbyqxmd.com/read/28141923/voltage-gating-of-a-biomimetic-nanopore-electrowetting-of-a-hydrophobic-barrier
#4
Jemma L Trick, Chen Song, E Jayne Wallace, Mark S P Sansom
It is desirable that nanopores that are components of biosensors are gated, i.e., capable of controllable switching between closed (impermeable) and open (permeable) states. A central hydrophobic barrier within a nanopore may act as a voltage-dependent gate via electrowetting, i.e., changes in nanopore surface wettability by application of an electric field. We use "computational electrophysiology" simulations to demonstrate and characterize electrowetting of a biomimetic nanopore containing a hydrophobic gate...
February 6, 2017: ACS Nano
https://www.readbyqxmd.com/read/28116358/dynamic-interactions-between-a-membrane-binding-protein-and-lipids-induce-fluctuating-diffusivity
#5
Eiji Yamamoto, Takuma Akimoto, Antreas C Kalli, Kenji Yasuoka, Mark S P Sansom
Pleckstrin homology (PH) domains are membrane-binding lipid recognition proteins that interact with phosphatidylinositol phosphate (PIP) molecules in eukaryotic cell membranes. Diffusion of PH domains plays a critical role in biological reactions on membrane surfaces. Although diffusivity can be estimated by long-time measurements, it lacks information on the short-time diffusive nature. We reveal two diffusive properties of a PH domain bound to the surface of a PIP-containing membrane using molecular dynamics simulations...
January 2017: Science Advances
https://www.readbyqxmd.com/read/28068080/effect-of-the-southeast-asian-ovalocytosis-deletion-on-the-conformational-dynamics-of-signal-anchor-transmembrane-segment-1-of-red-cell-anion-exchanger-1-ae1-band-3-or-slc4a1
#6
Philip W Fowler, Mark S P Sansom, Reinhart A F Reithmeier
The first transmembrane (TM1) helix in the red cell anion exchanger (AE1, Band 3, or SLC4A1) acts as an internal signal anchor that binds the signal recognition particle and directs the nascent polypeptide chain to the endoplasmic reticulum (ER) membrane where it moves from the translocon laterally into the lipid bilayer. The sequence N-terminal to TM1 forms an amphipathic helix that lies at the membrane interface and is connected to TM1 by a bend at Pro403. Southeast Asian ovalocytosis (SAO) is a red cell abnormality caused by a nine-amino acid deletion (Ala400-Ala408) at the N-terminus of TM1...
February 7, 2017: Biochemistry
https://www.readbyqxmd.com/read/28052056/genome-wide-in-vivo-screen-identifies-novel-host-regulators-of-metastatic-colonization
#7
Louise van der Weyden, Mark J Arends, Andrew D Campbell, Tobias Bald, Hannah Wardle-Jones, Nicola Griggs, Martin Del Castillo Velasco-Herrera, Thomas Tüting, Owen J Sansom, Natasha A Karp, Simon Clare, Diane Gleeson, Edward Ryder, Antonella Galli, Elizabeth Tuck, Emma L Cambridge, Thierry Voet, Iain C Macaulay, Kim Wong, Sarah Spiegel, Anneliese O Speak, David J Adams
Metastasis is the leading cause of death for cancer patients. This multi-stage process requires tumour cells to survive in the circulation, extravasate at distant sites, then proliferate; it involves contributions from both the tumour cell and tumour microenvironment ('host', which includes stromal cells and the immune system). Studies suggest the early steps of the metastatic process are relatively efficient, with the post-extravasation regulation of tumour growth ('colonization') being critical in determining metastatic outcome...
January 12, 2017: Nature
https://www.readbyqxmd.com/read/27993564/interfacial-activation-of-m37-lipase-a-multi-scale-simulation-study
#8
Nathalie Willems, Mickaël Lelimousin, Heidi Koldsø, Mark S P Sansom
Lipases are enzymes of biotechnological importance that function at the interface formed between hydrophobic and aqueous environments. Hydrophobic interfaces can induce structural transitions in lipases that result in an increase in enzyme activity, although the detailed mechanism of this process is currently not well understood for many lipases. Here, we present a multi-scale molecular dynamics simulation study of how different interfaces affect the conformational dynamics of the psychrophilic lipase M37. Our simulations show that M37 lipase is able to interact both with anionic lipid bilayers and with triglyceride surfaces...
March 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27974389/structure-and-lipid-binding-properties-of-the-kindlin-3-pleckstrin-homology-domain
#9
Tao Ni, Antreas C Kalli, Fiona B Naughton, Luke A Yates, Omar Naneh, Mirijam Kozorog, Gregor Anderluh, Mark S P Sansom, Robert J C Gilbert
Kindlins co-activate integrins alongside talin. They possess, like talin, a FERM domain (4.1-erythrin-radixin-moiesin domain) comprising F0-F3 subdomains, but with a pleckstrin homology (PH) domain inserted in the F2 subdomain that enables membrane association. We present the crystal structure of murine kindlin-3 PH domain determined at a resolution of 2.23 Å and characterise its lipid binding using biophysical and computational approaches. Molecular dynamics simulations suggest flexibility in the PH domain loops connecting β-strands forming the putative phosphatidylinositol phosphate (PtdInsP)-binding site...
February 15, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/27917824/on-the-interpretation-of-reflectivity-data-from-lipid-bilayers-in-terms-of-molecular-dynamics-models
#10
Arwel V Hughes, Fillip Ciesielski, Antreas C Kalli, Luke A Clifton, Timothy R Charlton, Mark S P Sansom, John R P Webster
Neutron and X-ray reflectivity of model membranes is increasingly used as a tool for the study of membrane structures and dynamics. As the systems under study become more complex, and as long, all-atom molecular-dynamics (MD) simulations of membranes become more available, there is increasing interest in the use of MD simulations in the analysis of reflectometry data from membranes. In order to perform this, it is necessary to produce a model of the complete interface, including not only the MD-derived structure of the membrane, but also the supporting substrate and any other interfacial layers that may be present...
December 1, 2016: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/27881707/a-cd80-biased-ctla4-ig-fusion-protein-with-superior-in-vivo-efficacy-by-simultaneous-engineering-of-affinity-selectivity-stability-and-fcrn-binding
#11
Julie Douthwaite, Jacques Moisan, Cyril Privezentzev, Blagoje Soskic, Shereen Sabbah, Suzanne Cohen, Andie Collinson, Elizabeth England, Catherine Huntington, Ben Kemp, Li Zhuang, Suzanne Hudak, D Gareth Rees, Debbie Goldberg, Chris Barton, Linda Chang, Inna Vainshtein, Meina Liang, Laurie Iciek, Philip Ambery, Mark Peakman, Tristan J Vaughan, Tim I M Tree, David M Sansom, Michael A Bowen, Ralph R Minter, Lutz Jermutus
Affinity- and stability-engineered variants of CTLA4-Ig fusion molecules with enhanced pharmacokinetic profiles could yield improved therapies with the potential of higher efficacy and greater convenience to patients. In this study, to our knowledge, we have, for the first time, used in vitro evolution to simultaneously optimize CTLA4 affinity and stability. We selected for improved binding to both ligands, CD80 and CD86, and screened as dimeric Fc fusions directly in functional assays to identify variants with stronger suppression of in vitro T cell activation...
January 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27866853/functional-annotation-of-ion-channel-structures-by-molecular-simulation
#12
Jemma L Trick, Sivapalan Chelvaniththilan, Gianni Klesse, Prafulla Aryal, E Jayne Wallace, Stephen J Tucker, Mark S P Sansom
Ion channels play key roles in cell membranes, and recent advances are yielding an increasing number of structures. However, their functional relevance is often unclear and better tools are required for their functional annotation. In sub-nanometer pores such as ion channels, hydrophobic gating has been shown to promote dewetting to produce a functionally closed (i.e., non-conductive) state. Using the serotonin receptor (5-HT3R) structure as an example, we demonstrate the use of molecular dynamics to aid the functional annotation of channel structures via simulation of the behavior of water within the pore...
December 6, 2016: Structure
https://www.readbyqxmd.com/read/27856273/hypermutation-in-pancreatic-cancer
#13
Jeremy L Humphris, Ann-Marie Patch, Katia Nones, Peter J Bailey, Amber L Johns, Skye McKay, David K Chang, David K Miller, Marina Pajic, Karin S Kassahn, Michael C J Quinn, Timothy J C Bruxner, Angelika N Christ, Ivon Harliwong, Senel Idrisoglu, Suzanne Manning, Craig Nourse, Ehsan Nourbakhsh, Andrew Stone, Peter J Wilson, Matthew Anderson, J Lynn Fink, Oliver Holmes, Stephen Kazakoff, Conrad Leonard, Felicity Newell, Nick Waddell, Scott Wood, Ronald S Mead, Qinying Xu, Jianmin Wu, Mark Pinese, Mark J Cowley, Marc D Jones, Adnan M Nagrial, Venessa T Chin, Lorraine A Chantrill, Amanda Mawson, Angela Chou, Christopher J Scarlett, Andreia V Pinho, Ilse Rooman, Marc Giry-Laterriere, Jaswinder S Samra, James G Kench, Neil D Merrett, Christopher W Toon, Krishna Epari, Nam Q Nguyen, Andrew Barbour, Nikolajs Zeps, Nigel B Jamieson, Colin J McKay, C Ross Carter, Euan J Dickson, Janet S Graham, Fraser Duthie, Karin Oien, Jane Hair, Jennifer P Morton, Owen J Sansom, Robert Grützmann, Ralph H Hruban, Anirban Maitra, Christine A Iacobuzio-Donahue, Richard D Schulick, Christopher L Wolfgang, Richard A Morgan, Rita T Lawlor, Borislav Rusev, Vincenzo Corbo, Roberto Salvia, Ivana Cataldo, Giampaolo Tortora, Margaret A Tempero, Oliver Hofmann, James R Eshleman, Christian Pilarsky, Aldo Scarpa, Elizabeth A Musgrove, Anthony J Gill, John V Pearson, Sean M Grimmond, Nicola Waddell, Andrew V Biankin
Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2...
January 2017: Gastroenterology
https://www.readbyqxmd.com/read/27807980/convergence-and-sampling-in-determining-free-energy-landscapes-for-membrane-protein-association
#14
Jan Domanski, George Hedger, Robert B Best, Phillip James Stansfeld, Mark S P Sansom
Potential of mean force (PMF) calculations are used to characterize the free energy landscape of protein-lipid and protein-protein association within membranes. Coarse-grained simulations allow binding free energies to be determined with reasonable statistical error. This accuracy relies on defining a good collective variable describing the binding and unbinding transition, and upon criteria for assessing the convergence of the simulation toward representative equilibrium sampling. As examples, we calculate protein-lipid binding PMFs for ANT/cardiolipin and Kir2...
November 3, 2016: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/27786441/lipid-loving-ants-molecular-simulations-of-cardiolipin-interactions-and-the-organization-of-the-adenine-nucleotide-translocase-in-model-mitochondrial-membranes
#15
George Hedger, Sarah L Rouse, Jan Domański, Matthieu Chavent, Heidi Koldsø, Mark S P Sansom
The exchange of ADP and ATP across the inner mitochondrial membrane is a fundamental cellular process. This exchange is facilitated by the adenine nucleotide translocase, the structure and function of which are critically dependent on the signature phospholipid of mitochondria, cardiolipin (CL). Here we employ multiscale molecular dynamics simulations to investigate CL interactions within a membrane environment. Using simulations at both coarse-grained and atomistic resolutions, we identify three CL binding sites on the translocase, in agreement with those seen in crystal structures and inferred from nuclear magnetic resonance measurements...
November 15, 2016: Biochemistry
https://www.readbyqxmd.com/read/27722554/membrane-stiffness-is-modified-by-integral-membrane-proteins
#16
Philip W Fowler, Jean Hélie, Anna Duncan, Matthieu Chavent, Heidi Koldsø, Mark S P Sansom
The ease with which a cell membrane can bend and deform is important for a wide range of biological functions. Peripheral proteins that induce curvature in membranes (e.g. BAR domains) have been studied for a number of years. Little is known, however, about the effect of integral membrane proteins on the stiffness of a membrane (characterised by the bending rigidity, Kc). We demonstrate by computer simulation that adding integral membrane proteins at physiological densities alters the stiffness of the membrane...
September 20, 2016: Soft Matter
https://www.readbyqxmd.com/read/27574865/roles-of-interleaflet-coupling-and-hydrophobic-mismatch-in-lipid-membrane-phase-separation-kinetics
#17
Philip W Fowler, John J Williamson, Mark S P Sansom, Peter D Olmsted
Characterizing the nanoscale dynamic organization within lipid bilayer membranes is central to our understanding of cell membranes at a molecular level. We investigate phase separation and communication across leaflets in ternary lipid bilayers, including saturated lipids with between 12 and 20 carbons per tail. Coarse-grained molecular dynamics simulations reveal a novel two-step kinetics due to hydrophobic mismatch, in which the initial response of the apposed leaflets upon quenching is to increase local asymmetry (antiregistration), followed by dominance of symmetry (registration) as the bilayer equilibrates...
September 14, 2016: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/27572256/proton-currents-constrain-structural-models-of-voltage-sensor-activation
#18
Aaron L Randolph, Younes Mokrab, Ashley L Bennett, Mark Sp Sansom, Ian Scott Ramsey
The Hv1 proton channel is evidently unique among voltage sensor domain proteins in mediating an intrinsic 'aqueous' H(+) conductance (GAQ). Mutation of a highly conserved 'gating charge' residue in the S4 helix (R1H) confers a resting-state H(+) 'shuttle' conductance (GSH) in VGCs and Ci VSP, and we now report that R1H is sufficient to reconstitute GSH in Hv1 without abrogating GAQ. Second-site mutations in S3 (D185A/H) and S4 (N4R) experimentally separate GSH and GAQ gating, which report thermodynamically distinct initial and final steps, respectively, in the Hv1 activation pathway...
August 30, 2016: ELife
https://www.readbyqxmd.com/read/27488650/pigmented-anatomy-in-carboniferous-cyclostomes-and-the-evolution-of-the-vertebrate-eye
#19
Sarah E Gabbott, Philip C J Donoghue, Robert S Sansom, Jakob Vinther, Andrei Dolocan, Mark A Purnell
The success of vertebrates is linked to the evolution of a camera-style eye and sophisticated visual system. In the absence of useful data from fossils, scenarios for evolutionary assembly of the vertebrate eye have been based necessarily on evidence from development, molecular genetics and comparative anatomy in living vertebrates. Unfortunately, steps in the transition from a light-sensitive 'eye spot' in invertebrate chordates to an image-forming camera-style eye in jawed vertebrates are constrained only by hagfish and lampreys (cyclostomes), which are interpreted to reflect either an intermediate or degenerate condition...
August 17, 2016: Proceedings. Biological Sciences
https://www.readbyqxmd.com/read/27465729/the-integrin-receptor-in-biologically-relevant-bilayers-insights-from-molecular-dynamics-simulations
#20
Antreas C Kalli, Tomasz Rog, Ilpo Vattulainen, Iain D Campbell, Mark S P Sansom
Integrins are heterodimeric (αβ) cell surface receptors that are potential therapeutic targets for a number of diseases. Despite the existence of structural data for all parts of integrins, the structure of the complete integrin receptor is still not available. We have used available structural data to construct a model of the complete integrin receptor in complex with talin F2-F3 domain. It has been shown that the interactions of integrins with their lipid environment are crucial for their function but details of the integrin/lipid interactions remain elusive...
July 27, 2016: Journal of Membrane Biology
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