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Molecular dynamics simulation channel

Beatrice N Markiewicz, Thomas Lemmin, Wenkai Zhang, Ismail A Ahmed, Hyunil Jo, Giacomo Fiorin, Thomas Troxler, William F DeGrado, Feng Gai
The M2 proton channel of the influenza A virus has been the subject of extensive studies because of its critical role in viral replication. As such, we now know a great deal about its mechanism of action, especially how it selects and conducts protons in an asymmetric fashion. The conductance of this channel is tuned to conduct protons at a relatively low biologically useful rate, which allows acidification of the viral interior of a virus entrapped within an endosome, but not so great as to cause toxicity to the infected host cell prior to packaging of the virus...
October 11, 2016: Physical Chemistry Chemical Physics: PCCP
Zuzana Benková, Pavol Námer, Peter Cifra
The combined effects of the channel asymmetry and the closed chain topology on the chain extension, structure factor, and the orientation correlations were studied using coarse-grained molecular dynamics simulations for moderate chain lengths. These effects are related to applications in linearization experiments with a DNA molecule in nanofluidic devices. According to the aspect ratio, the channels are classified as a stripe or slabs. The chain segments do not have any freedom to move in the direction of the narrowest stripe size, being approximately the same size as the segment size...
October 12, 2016: Soft Matter
Abishek Suresh, Andrew Hung
The α7 and α4β2 neuronal nicotinic receptors belonging to the family of ligand-gated ion channels are most prevalent in the brain, and are implicated in various neurodegenerative disorders. α-conotoxin GID (and its analogue [ϒ4E]GID) specifically inhibits these subtypes, with more affinity towards the human α7 (hα7) subtype, and is valuable in understanding the physiological roles of these receptors. In this study, we use umbrella-sampling molecular dynamics simulations to understand the mechanism of interaction between [ϒ4E]GID and the agonist binding pockets of the α4β2 and the hα7 receptors, and to estimate their relative binding affinities (ΔGbind)...
September 21, 2016: Journal of Molecular Graphics & Modelling
Isabelle Callebaut, Brice Hoffmann, Pierre Lehn, Jean-Paul Mornon
The cystic fibrosis transmembrane conductance regulator (CFTR) protein is a member of the ATP-binding cassette (ABC) transporter superfamily that functions as an ATP-gated channel. Considerable progress has been made over the last years in the understanding of the molecular basis of the CFTR functions, as well as dysfunctions causing the common genetic disease cystic fibrosis (CF). This review provides a global overview of the theoretical studies that have been performed so far, especially molecular modelling and molecular dynamics (MD) simulations...
October 7, 2016: Cellular and Molecular Life Sciences: CMLS
John D Lueck, Adam L Mackey, Daniel T Infield, Jason D Galpin, Jing Li, Benoît Roux, Christopher A Ahern
C-type inactivation of potassium channels fine-tunes the electrical signaling in excitable cells through an internal timing mechanism that is mediated by a hydrogen bond network in the channels' selectively filter. Previously, (Pless, 2013) we used nonsense suppression to highlight the role of the conserved Trp434-Asp447 indole hydrogen bond in Shaker potassium channels with a non-hydrogen bonding homologue of tryptophan, Ind. Here, molecular dynamics simulations indicate that the Trp434Ind hydrogen bonding partner, Asp447, unexpectedly 'flips out' towards the extracellular environment, allowing water to penetrate the space behind the selectivity filter while simultaneously reducing the local negative electrostatic charge...
October 6, 2016: ELife
Johannes Knorr, Pandian Sokkar, Sebastian Schott, Paolo Costa, Walter Thiel, Wolfram Sander, Elsa Sanchez-Garcia, Patrick Nuernberger
Photochemical reactions in solution often proceed via competing reaction pathways comprising intermediates that capture a solvent molecule. A disclosure of the underlying reaction mechanisms is challenging due to the rapid nature of these processes and the intricate identification of how many solvent molecules are involved. Here combining broadband femtosecond transient absorption and quantum mechanics/molecular mechanics simulations, we show for one of the most reactive species, diphenylcarbene, that the decision-maker is not the nearest solvent molecule but its neighbour...
October 6, 2016: Nature Communications
Amit Pathak
Epithelial-to-mesenchymal transition (EMT) enables scattering of cell clusters and disseminates motile cells to distant locations in vivo during embryonic development and cancer metastasis. Both stiffness and topography of the extracellular matrix (ECM) have been shown to influence EMT. In this work, we examine how the integrity of epithelial cell clusters is regulated by subcellular forces, protrusions, and adhesions for varying ECM inputs, such as stiffness, topography, and dimensionality. Our model simulates multicell networks of defined sizes and shapes in ECMs of varied stiffness and geometry...
October 4, 2016: Biophysical Journal
Huong T Kratochvil, Joshua K Carr, Kimberly Matulef, Alvin W Annen, Hui Li, Michał Maj, Jared Ostmeyer, Arnaldo L Serrano, H Raghuraman, Sean D Moran, J L Skinner, Eduardo Perozo, Benoît Roux, Francis I Valiyaveetil, Martin T Zanni
Potassium channels are responsible for the selective permeation of K(+) ions across cell membranes. K(+) ions permeate in single file through the selectivity filter, a narrow pore lined by backbone carbonyls that compose four K(+) binding sites. Here, we report on the two-dimensional infrared (2D IR) spectra of a semisynthetic KcsA channel with site-specific heavy ((13)C(18)O) isotope labels in the selectivity filter. The ultrafast time resolution of 2D IR spectroscopy provides an instantaneous snapshot of the multi-ion configurations and structural distributions that occur spontaneously in the filter...
September 2, 2016: Science
Jun Wei Li, Shao Ying Xiao, Xiao Xiao Xie, Hui Zhou, Chun Li Pang, Shan Shan Li, Hai Lin Zhang, Diomedes E Logothetis, Yong Zhan, Hai Long An
Kir2.1 (also known as IRK1) plays key roles in regulation of resting membrane potential and cell excitability. To achieve its physiological roles, Kir2.1 performs a series of conformational transition, named as gating. However, the structural basis of gating is still obscure. Here, we combined site-directed mutation, two-electrode voltage clamp with molecular dynamics simulations and determined that H221 regulates the gating process of Kir2.1 by involving a weak interaction network. Our data show that the H221R mutant accelerates the rundown kinetics and decelerates the reactivation kinetics of Kir2...
October 3, 2016: Proteins
Han Wen, Feng Qin, Wenjun Zheng
As a key cellular sensor, the TRPV1 cation channel undergoes a gating transition from a closed state to an open state in response to various physical and chemical stimuli including noxious heat. Despite years of study, the heat activation mechanism of TRPV1 gating remains enigmatic at the molecular level. Toward elucidating the structural and energetic basis of TRPV1 gating, we have performed molecular dynamics (MD) simulations (with cumulative simulation time of 3 μs), starting from the high-resolution closed and open structures of TRPV1 solved by cryo-electron microscopy...
October 3, 2016: Proteins
Jinfeng Teng, Stephen H Loukin, Andriy Anishkin, Ching Kung
We have some generalized physical understanding of how ion channels interact with surrounding lipids but few detailed descriptions on how interactions of particular amino acids with contacting lipids may regulate gating. Here we discovered a structure-specific interaction between an amino acid and inner-leaflet lipid that governs the gating transformations of TRPV4 (transient receptor potential vanilloid type 4). Many cation channels use a S4-S5 linker to transmit stimuli to the gate. At the start of TRPV4's linker helix is leucine 596...
October 3, 2016: Proceedings of the National Academy of Sciences of the United States of America
Benjamin L Timney, Barak Raveh, Roxana Mironska, Jill M Trivedi, Seung Joong Kim, Daniel Russel, Susan R Wente, Andrej Sali, Michael P Rout
Passive macromolecular diffusion through nuclear pore complexes (NPCs) is thought to decrease dramatically beyond a 30-60-kD size threshold. Using thousands of independent time-resolved fluorescence microscopy measurements in vivo, we show that the NPC lacks such a firm size threshold; instead, it forms a soft barrier to passive diffusion that intensifies gradually with increasing molecular mass in both the wild-type and mutant strains with various subsets of phenylalanine-glycine (FG) domains and different levels of baseline passive permeability...
October 10, 2016: Journal of Cell Biology
Lizhe Zhu, Hanlun Jiang, Fu Kit Sheong, Xuefeng Cui, Yanli Wang, Xin Gao, Xuhui Huang
At the core of RNA interference, the Argonaute proteins (Ago) load and utilize small guide nucleic acids to silence mRNAs or cleave foreign nucleic acids in a sequence specific manner. In recent years, based on extensive structural studies of Ago and its interaction with the nucleic acids, considerable progress has been made to reveal the dynamic aspects of various Ago-mediated processes. Here we review these novel insights into the guide-strand loading, duplex unwinding, and effects of seed mismatch, with a focus on two representative Agos, the human Ago 2 (hAgo2) and the bacterial Thermus thermophilus Ago (TtAgo)...
September 30, 2016: Progress in Biophysics and Molecular Biology
Zhi-Gang Huang, Hao-Wen Liu, Zhen-Zhen Yan, Sheng Wang, Lu-Yang Wang, Jiu-Ping Ding
Large-conductance Ca(2+)- and voltage- activated potassium (MaxiK or BK) channels are composed of a pore-forming α subunit (Slo) and four types of auxiliary β subunits or just a pore-forming α subunit. Although multiple N-linked glycosylation sites in the extracellular loop of β subunits have been identified, very little is known about how glycosylation influences the structure and function of BK channels. Using a combination of site-directed mutagenesis, western blot and patch-clamp recordings, we demonstrated that three sites in the extracellular loop of β2 subunit are N-glycosylated (N-X-T/S at N88, N96 and N119)...
October 3, 2016: Channels
Bryan VanSchouwen, Giuseppe Melacini
The hyperpolarization-activated cyclic-nucleotide-modulated (HCN) ion channels control rhythmicity in neurons and cardiomyocytes. Cyclic AMP (cAMP) modulates HCN activity through cAMP-dependent formation of a tetrameric gating ring spanning the intracellular region (IR) of HCN. In the absence of cAMP, the IR cAMP-binding domain (CBD) mainly samples its inactive conformation, resulting in steric clashes that destabilize the IR tetramer. Although these clashes with the inactive CBD are released through tetramer dissociation into monomers, functional mutagenesis suggests that the apo IR is not fully monomeric...
October 3, 2016: Journal of Physical Chemistry. B
Pradeep Sathyanarayana, Rajat Desikan, K Ganapathy Ayappa, Sandhya S Visweswariah
Pore-forming toxins (PFTs) bind to cell membranes and form nanoscale pores that allow leakage of cellular components, resulting in cell death. The water-soluble, monomeric form of these toxins shows a dramatic conformational change during pore formation, as exemplified by crystal structures of the monomer and functional pore of cytolysin A (ClyA). The solvent-exposed, C-terminal residues of the protein are essential for activity, but the mechanism by which this region regulates pore formation remains unknown...
October 13, 2016: Biochemistry
Balasundaresan Dhakshnamoorthy, Ahmed Rohaim, Huan Rui, Lydia Blachowicz, Benoît Roux
The selectivity filter is an essential functional element of K(+) channels that is highly conserved both in terms of its primary sequence and its three-dimensional structure. Here, we investigate the properties of an ion channel from the Gram-positive bacterium Tsukamurella paurometabola with a selectivity filter formed by an uncommon proline-rich sequence. Electrophysiological recordings show that it is a non-selective cation channel and that its activity depends on Ca(2+) concentration. In the crystal structure, the selectivity filter adopts a novel conformation with Ca(2+) ions bound within the filter near the pore helix where they are coordinated by backbone oxygen atoms, a recurrent motif found in multiple proteins...
2016: Nature Communications
James B Fields, Karin L Németh-Cahalan, J Alfredo Freites, Irene Vorontsova, James E Hall, Douglas J Tobias
Aquaporin 0 (AQP0), the major intrinsic protein of the eye lens, plays a vital role in maintaining lens clarity by facilitating the transport of water across lens fiber cell membranes. AQP0 reduces its osmotic water permeability constant (Pf) in response to increases in the external calcium concentration, an effect that is mediated by an interaction with the calcium-binding messenger protein, calmodulin (CaM), and phosphorylation of the CaM binding site abolishes calcium sensitivity. Despite recent structural characterization of the AQP0-CaM complex, the mechanism by which CaM modulates AQP0 remains poorly understood...
September 22, 2016: Journal of Biological Chemistry
Truong Quoc Vo, BoHung Kim
In molecular-level fluidic transport, where the discrete characteristics of a molecular system are not negligible (in contrast to a continuum description), the response of the molecular water system might still be similar to the continuum description if the time and ensemble averages satisfy the ergodic hypothesis and the scale of the average is enough to recover the classical thermodynamic properties. However, even in such cases, the continuum description breaks down on the material interfaces. In short, molecular-level liquid flows exhibit substantially different physics from classical fluid transport theories because of (i) the interface/surface force field, (ii) thermal/velocity slip, (iii) the discreteness of fluid molecules at the interface and (iv) local viscosity...
2016: Scientific Reports
Wei Chen, Yandong Huang, Jana Shen
Proton-coupled transmembrane proteins play important roles in human health and diseases; however, detailed mechanisms are often elusive. Experimentally resolving proton positions and structural details is challenging, and conventional molecular dynamics simulations are performed with preassigned and fixed protonation states. To address this challenge, here we illustrate the use of the state-of-the-art continuous constant pH molecular dynamics (CpHMD) to directly describe the activation of the M2 channel of influenza virus, for which abundant experimental data are available...
October 6, 2016: Journal of Physical Chemistry Letters
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