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https://www.readbyqxmd.com/read/28211063/gating-energetics-of-a-voltage-dependent-k-channel-pore-domain
#1
Greg Starek, J Alfredo Freites, Simon Bernèche, Douglas J Tobias
We used targeted molecular dynamics, informed by experimentally determined inter-atomic distances defining the pore region of open and closed states of the KvAP voltage-gated potassium channel, to generate a gating pathway of the pore domain in the absence of the voltage-sensing domains. We then performed umbrella sampling simulations along this pathway to calculate a potential of mean force that describes the free energy landscape connecting the closed and open conformations of the pore domain. The resulting energetic landscape displays three minima, corresponding to stable open, closed, and intermediate conformations with roughly similar stabilities...
February 16, 2017: Journal of Computational Chemistry
https://www.readbyqxmd.com/read/28206745/atomistic-molecular-dynamics-simulations-of-mitochondrial-dna-polymerase-gamma-novel-mechanisms-of-function-and-pathogenesis
#2
Liliya Euro, Outi Haapanen, Tomasz Rog, Ilpo Vattulainen, Anu Suomalainen, Vivek Sharma
DNA polymerase gamma (Pol γ) is a key component of the mitochondrial DNA replisome and an important cause of neurological diseases. Despite the availability of its crystal structures, the molecular mechanism of DNA replication, the switch between polymerase and exonuclease activities, the site of replisomal interactions and functional effects of patient mutations that do not affect direct catalysis have remained elusive. Here we report first atomistic classical molecular dynamics (MD) simulations of human Pol γ replicative complex...
February 16, 2017: Biochemistry
https://www.readbyqxmd.com/read/28197074/the-first-extracellular-linker-is-important-for-several-aspects-of-the-gating-mechanism-of-human-trpa1-channel
#3
Lenka Marsakova, Ivan Barvik, Vlastimil Zima, Lucie Zimova, Viktorie Vlachova
Transient receptor potential ankyrin 1 (TRPA1) is an excitatory ion channel involved in pain, inflammation and itching. This channel gates in response to many irritant and proalgesic agents, and can be modulated by calcium and depolarizing voltage. While the closed-state structure of TRPA1 has been recently resolved, also having its open state is essential for understanding how this channel works. Here we use molecular dynamics simulations combined with electrophysiological measurements and systematic mutagenesis to predict and explore the conformational changes coupled to the expansion of the presumptive channel's lower gate...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28195288/slip-divergence-of-water-flow-in-graphene-nanochannels-the-role-of-chirality
#4
Enrique Wagemann, Elton Oyarzua, Jens H Walther, Harvey A Zambrano
Graphene has attracted considerable attention due to its characteristics as a 2D material and its fascinating properties, providing a potential building block for nanofabrication. In nanochannels the solid-liquid interface plays a non-negligible role in determining the fluid dynamics. Therefore, for an optimal design of nanofluidic devices, a comprehensive understanding of the slippage in a water flow confined between graphene walls is important. In nanoconfinement, experimental and computational studies have found the slip length to increase nonlinearly when the shear rate is larger than a critical value...
February 14, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28194851/inversion-of-the-side-chain-stereochemistry-of-indvidual-thr-or-ile-residues-in-a-protein-molecule-impact-on-the-folding-stability-and-structure-of-the-shk-toxin
#5
Bobo Dang, Rong Shen, Tomoya Kubota, Kalyaneswar Mandal, Francisco Bezanilla, Benoit Roux, Stephen B H Kent
ShK toxin is a cysteine-rich 35-residue protein ion-channel ligand isolated from the sea anemone Stichodactyla helianthus. In this work, we studied the effect of inverting the side chain stereochemistry of individual Thr or Ile residues on the properties of the ShK protein. Molecular dynamics simulations were used to calculate the free energy cost of inverting the side-chain stereochemistry of individual Thr or Ile residues. Guided by the computational results, we used chemical protein synthesis to prepare three ShK polypeptide chain analogues, each containing either an allo-Thr or an allo-Ile residue...
February 14, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28188741/molecular-dynamics-study-of-ion-transport-through-an-open-model-of-voltage-gated-sodium-channel
#6
Yang Li, Ruining Sun, Huihui Liu, Haipeng Gong
Voltage-gated sodium (NaV) channels are critical in the signal transduction of excitable cells. In this work, we modeled the open conformation for the pore domain of a prokaryotic NaV channel (NaVRh), and used molecular dynamics simulations to track the translocation of dozens of Na(+) ions through the channel in the presence of a physiological transmembrane ion concentration gradient and a transmembrane electrical field that was closer to the physiological one than previous studies. Channel conductance was then estimated from simulations on the wide-type and DEKA mutant of NaVRh...
February 8, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28186717/gating-motions-and-stationary-gating-properties-of-ionotropic-glutamate-receptors-computation-meets-electrophysiology
#7
Huan-Xiang Zhou
Ionotropic glutamate receptors (iGluRs) are tetrameric ligand-gated ion channels essential to all aspects of brain function, including higher order processes such as learning and memory. For decades, electrophysiology was the primary means for characterizing the function of iGluRs and gaining mechanistic insight. Since the turn of the century, structures of isolated water-soluble domains and transmembrane-domain-containing constructs have provided the basis for formulating mechanistic hypotheses. Because these structures only represent sparse, often incomplete snapshots during iGluR activation, significant gaps in knowledge remain regarding structures, energetics, and dynamics of key substates along the functional processes...
February 10, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28186490/atomistic-simulations-indicate-the-c-subunit-ring-of-the-f1fo-atp-synthase-is-not-the-mitochondrial-permeability-transition-pore
#8
Wenchang Zhou, Fabrizio Marinelli, Corrine Nief, José D Faraldo-Gómez
Pathological metabolic conditions such as ischemia induce the rupture of the mitochondrial envelope and the release of pro-apoptotic proteins, leading to cell death. At the onset of this process, the inner mitochondrial membrane becomes depolarized and permeable to osmolytes, due to the opening of a non-selective protein channel of unknown molecular identity. A recent study purports that this channel, referred to as Mitochondrial Permeability Transition Pore (MPTP), is the lumen of the c-subunit ring of the ATP synthase, upon dissociation from the catalytic domain...
February 10, 2017: ELife
https://www.readbyqxmd.com/read/28178811/translational-diffusion-of-proteins-in-nanochannels
#9
Sridhar Kumar Kannam, Matthew T Downton
Hydrodynamic interactions play an important role in the transport of analytes through nanoscale devices. Of particular note is the role that no-slip boundary conditions have on the drag coefficient of confined particles and molecules. In this work, we use a coarse grained molecular dynamics model to measure the diffusion coefficients of proteins confined within cylindrical nanochannels of similar dimension. Finite-size corrected bulk diffusion coefficients are found to agree with experimental data, while in channels, a good match is found between theoretical expressions based on continuum fluid mechanics and the reduction of the translational diffusion coefficient across a range of protein to channel size ratios...
February 7, 2017: Journal of Chemical Physics
https://www.readbyqxmd.com/read/28151682/molecular-simulation-of-the-ions-ultraconfined-in-the-nanometer-channel-of-calcium-silicate-hydrate-hydration-mechanism-dynamic-properties-and-influence-on-the-cohesive-strength
#10
Dongshuai Hou, Chuanlin Hu, Zongjin Li
Reactive force field molecular dynamics was utilized to investigate the structure, dynamics, and mechanical nature of different cations solvated in the nanometer-channel of highly disordered calcium silicate hydrate. The local structures of different cations bonded with hydroxyl groups are characterized by the long spatial correlation, bond angel distribution preference, and featured coordinated number, resembling those of the tetra-/penta-/octahedron for cation-oxygen structure in the defective region of the silicate glass...
February 20, 2017: Inorganic Chemistry
https://www.readbyqxmd.com/read/28151650/molecular-dynamics-simulations-of-membrane-bound-stim1-to-investigate-conformational-changes-during-stim1-activation-upon-calciumrelease
#11
Sreya Mukherjee, Aleksandra Karolak, Marjolaine Debant, Paul Buscaglia, Yves Renaudineau, Olivier Mignen, Wayne Charles Guida, Wesley H Brooks
Calcium is involved in important intracellular processes, such as intracellular signaling from cell membrane receptors to the nucleus. Typically calcium levels are kept at less than 100 nM in the nucleus and cytosol but some calcium is stored in the endoplasmic reticulum (ER) lumen for rapid release to activate intracellular calcium-dependent functions. Stromal Interacting Molecule 1 (STIM1) plays a critical role in early sensing of changes in the ER's calcium level, especially when there is a sudden release of stored calcium from the ER...
February 2, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28150511/investigation-of-pde5-pde6-and-pde5-pde11-selective-potent-tadalafil-like-pde5-inhibitors-using-combination-of-molecular-modeling-approaches-molecular-fingerprint-based-virtual-screening-protocols-and-structure-based-pharmacophore-development
#12
Gülru Kayık, Nurcan Ş Tüzün, Serdar Durdagi
The essential biological function of phosphodiesterase (PDE) type enzymes is to regulate the cytoplasmic levels of intracellular second messengers, 3',5'-cyclic guanosine monophosphate (cGMP) and/or 3',5'-cyclic adenosine monophosphate (cAMP). PDE targets have 11 isoenzymes. Of these enzymes, PDE5 has attracted a special attention over the years after its recognition as being the target enzyme in treating erectile dysfunction. Due to the amino acid sequence and the secondary structural similarity of PDE6 and PDE11 with the catalytic domain of PDE5, first-generation PDE5 inhibitors (i...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
https://www.readbyqxmd.com/read/28147543/langevin-poisson-eqt-a-dipolar-solvent-based-quasi-continuum-approach-for-electric-double-layers
#13
S Y Mashayak, N R Aluru
Water is a highly polar solvent. As a result, electrostatic interactions of interfacial water molecules play a dominant role in determining the distribution of ions in electric double layers (EDLs). Near a surface, an inhomogeneous and anisotropic arrangement of water molecules gives rise to pronounced variations in the electrostatic and hydration energies of ions. Therefore, a detailed description of the structural and dielectric properties of water is important to study EDLs. However, most theoretical models ignore the molecular effects of water and treat water as a background continuum with a uniform dielectric permittivity...
January 28, 2017: Journal of Chemical Physics
https://www.readbyqxmd.com/read/28128570/potential-of-mean-force-calculations-of-solute-permeation-across-ut-b-and-aqp1-a-comparison-between-molecular-dynamics-and-3d-rism
#14
Igor Ariz-Extreme, Jochen S Hub
Membrane channels facilitate the efficient and selective flux of various solutes across biological membranes. A common approach to investigate the selectivity of a channel has been the calculation of potentials of mean force (PMFs) for solute permeation across the pore. PMFs have been frequently computed from molecular dynamics (MD) simulations, yet the three-dimensional reference interaction site model (3D-RISM) has been suggested as a computationally efficient alternative to MD. Whether the two methods yield comparable PMFs for solute permeation has remained unclear...
January 27, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28128447/trpc2-pseudogenization-dynamics-in-bats-reveal-ancestral-vomeronasal-signaling-then-pervasive-loss
#15
Laurel R Yohe, Ramatu Abubakar, Christina Giordano, Elizabeth Dumont, Karen Sears, Stephen J Rossiter, Liliana M Dávalos
Comparative methods are often used to infer loss or gain of complex phenotypes, but few studies take advantage of genes tightly linked with complex traits to test for shifts in the strength of selection. In mammals vomerolfaction detects chemical cues mediating many social and reproductive behaviors and is highly conserved, but all bats exhibit degraded vomeronasal structures with the exception of two families (Phyllostomidae and Miniopteridae). These families either regained vomerolfaction after ancestral loss, or there were many independent losses after diversification from an ancestor with functional vomerolfaction...
January 27, 2017: Evolution; International Journal of Organic Evolution
https://www.readbyqxmd.com/read/28122455/high-throughput-simulations-reveal-membrane-mediated-effects-of-alcohols-on-mscl-gating
#16
Manuel N Melo, Clément Arnarez, Hendrik Sikkema, Neeraj Kumar, Martin Walko, Herman J C Berendsen, Armagan Kocer, Siewert J Marrink, Helgi I Ingólfsson
The mechanosensitive channels of large conductance (MscL) are bacterial membrane proteins that serve as last resort emergency release valves in case of severe osmotic downshock. Sensing bilayer tension, MscL channels are sensitive to changes in the bilayer environment and are, therefore, an ideal test case for exploring membrane protein coupling. Here, we use high-throughput coarse-grained molecular dynamics simulations to characterize MscL gating kinetics in different bilayer environments under the influence of alcohols...
February 10, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28109880/dynamics-of-the-eag1-k-channel-selectivity-filter-assessed-by-molecular-dynamics-simulations
#17
Harald Bernsteiner, Michael Bründl, Anna Stary-Weinzinger
EAG1 channels belong to the KCNH family of voltage gated potassium channels. They are expressed in several brain regions and increased expression is linked to certain cancer types. Recent cryo-EM structure determination finally revealed the structure of these channels in atomic detail, allowing computational investigations. In this study, we performed molecular dynamics simulations to investigate the ion binding sites and the dynamical behavior of the selectivity filter. Our simulations suggest that sites S2 and S4 form stable ion binding sites, while ions placed at sites S1 and S3 rapidly switched to sites S2 and S4...
January 19, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28109223/ab-initio-study-of-several-static-and-dynamic-properties-of-bulk-liquid-ni-near-melting
#18
B G Del Rio, L E González, D J González
Several static and dynamic properties of bulk liquid Ni at a thermodynamic state near its triple point have been evaluated by ab initio molecular dynamics simulations. The calculated static structure shows very good agreement with the available experimental data, including an asymmetric second peak in the static structure factor, which underlines a marked local icosahedral short-range order in the liquid. The dynamical structure reveals propagating density fluctuations, and the calculated dynamic structure factors, S(q,ω), show a good agreement with the inelastic x-ray scattering measurements...
January 21, 2017: Journal of Chemical Physics
https://www.readbyqxmd.com/read/28108595/identification-of-the-adpr-binding-pocket-in-the-nudt9-homology-domain-of-trpm2
#19
Peilin Yu, Xiwen Xue, Jianmin Zhang, Xupang Hu, Yan Wu, Lin-Hua Jiang, Hongwei Jin, Jianhong Luo, Liangren Zhang, Zhenming Liu, Wei Yang
Activation of the transient receptor potential melastatin 2 (TRPM2) channel occurs during the response to oxidative stress under physiological conditions as well as in pathological processes such as ischemia and diabetes. Accumulating evidence indicates that adenosine diphosphate ribose (ADPR) is the most important endogenous ligand of TRPM2. However, although it is known that ADPR binds to the NUDT9 homology (NUDT9-H) domain in the intracellular C-terminal region, the molecular mechanism underlying ADPR binding and activation of TRPM2 remains unknown...
February 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/28107633/binding-and-proton-blockage-by-amantadine-variants-of-the-influenza-m2wt-and-m2s31n-explained
#20
Christina Tzitzoglaki, Anna Wright, Kathrin Freudenberger, Anja Hoffmann, Ian Tietjen, Ioannis Stylianakis, Felix Kolarov, David Fedida, Michaela Schmidtke, Günter Gauglitz, Timothy A Cross, Antonios Kolocouris
While aminoadamantanes are well-established inhibitors of the influenza A M2 proton channel, the mechanisms by which they are rendered ineffective against M2S31N are unclear. Solid state NMR, isothermal titration calorimetry, electrophysiology, antiviral assays, and molecular dynamics simulations suggest stronger binding interactions for aminoadamantanes to M2WT compared to negligible or weak binding to M2S31N. This is due to reshaping of the M2 pore when N31 is present, which, in contrast to wild-type (WT), leads (A) to the loss of the V27 pocket for the adamantyl cage and to a predominant orientation of the ligand's ammonium group toward the N-terminus and (B) to the lack of a helical kink upon ligand binding...
February 15, 2017: Journal of Medicinal Chemistry
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