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Molecular dynamics simulation channel

Dehbia Benkerrou, Matteo Ceccarelli
One of the greatest health threats facing modern medicine is the emergence of new bacterial strains which are increasingly resistant to almost all currently available antibiotics. According to a CDC (Center for Disease Control and Prevention) report published in 2013, 63% of Acinetobacter species have been identified as Multidrug resistant strains. As for other Gram-negative bacteria, the presence of an outer membrane increases the intrinsic resistance of A. baumannii to most antibiotics. The outer membrane of A...
March 15, 2018: Physical Chemistry Chemical Physics: PCCP
Antonios Drakopoulos, Christina Tzitzoglaki, Kelly McGuire, Anja Hoffmann, Athina Konstantinidi, Dimitrios Kolokouris, Chunlong Ma, Kathrin Freudenberger, Johanna Hutterer, Günter Gauglitz, Jun Wang, Michaela Schmidtke, David D Busath, Antonios Kolocouris
Recently, the binding kinetics of a ligand-target interaction, such as the residence time of a small molecule on its protein target, are seen as increasingly important for drug efficacy. Here, we investigate these concepts to explain binding and proton blockage of rimantadine variants bearing progressively larger alkyl groups to influenza A virus M2 wild type (WT) and M2 S31N protein proton channel. We showed that resistance of M2 S31N to rimantadine analogues compared to M2 WT resulted from their higher k off rates compared to the k on rates according to electrophysiology (EP) measurements...
March 8, 2018: ACS Medicinal Chemistry Letters
Pi Liu, Yan Zhao, Xiaoguo Liu, Jixue Sun, Dede Xu, Yang Li, Qian Li, Lihua Wang, Sichun Yang, Chunhai Fan, Jianping Lin
Shape reconfiguration of membrane protein channels is highly regulated under physiological conditions for gated transportation. Nevertheless, mechanistic understanding of molecular channels remains challenging due to the difficulty in probing gating-associated subtle structural changes. Here we show that charge neutralization can drive shape reconfiguration of a biomimetic 6-helix bundle DNA nanotube (6HB). Specifically, 6HB adopts a compact state when being neutralized by Mg2+; and monovalent ions (Na+) switch it to the expansion state, as revealed by molecular dynamics (MD) simulation, small angle X-ray scattering (SAXS) and Förster resonance energy transfer (FRET) characterization...
March 12, 2018: Angewandte Chemie
Kaliappan Muthukumar, Harald O Jeschke, Roser Valentí
The interaction of trimethyl(methylcyclopentadienyl)platinum(IV) ((C5 H4 CH3 )Pt(CH3 )3 ) molecules on fully and partially hydroxylated SiO2 surfaces, as well as the dynamics of this interaction were investigated using density functional theory (DFT) and finite temperature DFT-based molecular dynamics simulations. Fully and partially hydroxylated surfaces represent substrates before and after electron beam treatment and this study examines the role of electron beam pretreatment on the substrates in the initial stages of precursor dissociation and formation of Pt deposits...
2018: Beilstein Journal of Nanotechnology
Marc A Dämgen, Philip C Biggin
Many proteins that are central to key aspects of neurobiology undergo conformational changes as part of their function, usually in response to a stimulus. Often, these proteins are embedded within a membrane, which creates particular experimental challenges to surmount. This has resulted in computational methods providing a valuable complementary tool for some time now, especially in the development of working models at atomic resolution. Indeed, molecular dynamics MD) simulations are now routinely applied to new structures, either as part of the initial analysis or as part of an automated pipeline...
March 5, 2018: Neuroscience Letters
Jan Chalabala, Frank Uhlig, Petr Slavicek
Ionization in the condensed phase and molecular clusters leads to a complicated chain of processes with coupled electron-nuclear dynamics. It is difficult to describe such dynamics with conventional nonadiabatic molecular dynamics schemes since the number of states swiftly increases as the molecular system grows. It is therefore attractive to use a direct electron and nuclear propagation such as the real-time time-dependent density functional theory (RT-TDDFT). Here we report a RT-TDDFT benchmark study on simulations of singly and doubly-ionized states of a water monomer and dimer as a prototype for more complex processes in a condensed phase...
March 7, 2018: Journal of Physical Chemistry. A
Wei Chen, Shuyu Chen, Tengfei Liang, Qiang Zhang, Zhongli Fan, Hang Yin, Kuo-Wei Huang, Xixiang Zhang, Zhiping Lai, Ping Sheng
Freshwater flux and energy consumption are two important benchmarks for the membrane desalination process. Here, we show that nanoporous carbon composite membranes, which comprise a layer of porous carbon fibre structures grown on a porous ceramic substrate, can exhibit 100% desalination and a freshwater flux that is 3-20 times higher than existing polymeric membranes. Thermal accounting experiments demonstrated that the carbon composite membrane saved over 80% of the latent heat consumption. Theoretical calculations combined with molecular dynamics simulations revealed the unique microscopic process occurring in the membrane...
March 5, 2018: Nature Nanotechnology
Damodara N Reddy, Sukrit Singh, Chris M W Ho, Janki Patel, Paul Schlesinger, Stephen Rodgers, Allan Doctor, Garland R Marshall
Gramicidin A, a topical antibiotic made from alternating L and D amino acids, is characterized by its wide central pore; upon insertion into membranes, it forms channels that disrupts ion gradients. We present helical peptidomimetics with this characteristic wide central pore that have been designed to mimic gramicidin A channels. Mimetics were designed using molecular modeling focused on oligomers of heterochiral dipeptides of proline analogs, in particular azaproline (AzPro). Molecular Dynamics simulations in water confirmed the stability of the designed helices...
February 20, 2018: European Journal of Medicinal Chemistry
Chang Seon Lee, Moon-Ki Choi, Ye Young Hwang, Hyunki Kim, Moon Ki Kim, Yun Jung Lee
Water purification by membranes is widely investigated to address concerns related to the scarcity of clean water. Achieving high flux and rejection simultaneously is a difficult challenge using such membranes because these properties are mutually exclusive in common artificial membranes. Nature has developed a method for this task involving water-channel membrane proteins known as aquaporins. Here, the design and fabrication of graphene oxide (GO)-based membranes with a surface-tethered peptide motif designed to mimic the water-selective filter of natural aquaporins is reported...
February 27, 2018: Advanced Materials
Jing-Rong Fan, Heng Li, Hong-Xing Zhang, Qing-Chuan Zheng
The majority of cytochromes P450 play a critical role in metabolism of endogenous and exogenous substrates, some of its products are carcinogens. Therefore, inhibition of P450 enzymes activity can promote the detoxification and elimination of chemical carcinogens. In this study, molecular dynamics (MD) simulations and adaptive steered molecular dynamics (ASMD) simulations were performed to explore the structure features and channel dynamics of three P450 isoforms 2A6, 2A13, and 2E1 bound with the common inhibitor pilocarpine...
February 27, 2018: Biopolymers
James Krieger, Ji Young Lee, Ingo H Greger, Ivet Bahar
Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that are key players in synaptic transmission and plasticity. They are composed of four subunits, each containing four functional domains, the quaternary packing and collective structural dynamics of which are important determinants of their molecular mechanism of function. With the explosion of structural studies on different members of the family, including the structures of activated open channels, the mechanisms of action of these central signaling machines are now being elucidated...
February 23, 2018: Neuroscience Letters
Alma E V Andersson, Marina A Kasimova, Lucie Delemotte
Viral potassium channels (Kcv) are homologous to the pore module of complex [Formula: see text]-selective ion channels of cellular organisms. Due to their relative simplicity, they have attracted interest towards understanding the principles of [Formula: see text] conduction and channel gating. In this work, we construct a homology model of the [Formula: see text] open state, which we validate by studying the binding of known blockers and by monitoring ion conduction through the channel. Molecular dynamics simulations of this model reveal that the re-orientation of selectivity filter carbonyl groups coincides with the transport of potassium ions, suggesting a possible mechanism for fast gating...
February 23, 2018: Journal of Membrane Biology
Amanda Buyan, Delin Sun, Ben Corry
Voltage-gated sodium channels are essential for carrying electrical signals throughout the body, and mutations in these proteins are responsible for a variety of disorders, including epilepsy and pain syndromes. As such, they are the target of a number of drugs used for reducing pain or combatting arrhythmias and seizures. However, these drugs affect all sodium channel subtypes found in the body. Designing compounds to target select sodium channel subtypes will provide a new therapeutic pathway and would maximize treatment efficacy while minimizing side effects...
February 21, 2018: Proceedings of the National Academy of Sciences of the United States of America
Daniel Șterbuleac, Călin Lucian Maniu
The binding modes of many hERG ion channel blockers are well understood, but a notable exception is clofilium, a potent antiarrhythmic agent whose action relies on blocking the current mediated by hERG. From the previously hypothesized binding modes of clofilium to hERG, only two can explain most of the experimental results. In this study, computer simulations are performed in order to analyze the hypothesized binding modes and to identify the consensus one. This is accomplished by employing molecular dynamics (MD) simulations and interaction energy calculations...
February 21, 2018: Molecular Informatics
Bo Chen, Haifeng Jiang, Xiang Liu, Xuejiao Hu
Understanding the mechanism of water transport inside an interlayer between graphene-based plates has tremendous value for theoretical studies and industrial applications. The fluid flow confined in nano-scaled spaces experiences a slip velocity near the wall, which is significantly different to that of bulk water. Here we propose a model combining classic hydrodynamics with kinetic theory to depict the dependency of the slip effect on the oxide concentration of valley plates. The influence of oxidized graphene on water flow is a comprehensive result of a slipped boundary, and depends on both the diffuse reflection coefficient of the wall, and the shrunken effective passageway caused by the electrostatic interactions between the oxidized surface and the water molecules...
February 21, 2018: Physical Chemistry Chemical Physics: PCCP
Bryan VanSchouwen, Giuseppe Melacini
Hyperpolarization-activated cyclic-nucleotide-modulated (HCN) ion channels control rhythmicity in neurons and cardiomyocytes. Cyclic AMP (cAMP) modulates HCN activity through the cAMP-induced formation of a tetrameric gating ring spanning the intracellular region (IR) of HCN. Although evidence from confocal patch-clamp fluorometry indicates that the cAMP-dependent gating of HCN occurs through a dimer of dimers, the structural and dynamical basis of cAMP allostery in HCN dimers has so far remained elusive. Thus, here we examine how dimers influence IR structural dynamics, and the role that such structural dynamics play in HCN allostery...
February 20, 2018: Journal of Physical Chemistry. B
Chaowei Shi, Yao He, Kitty Hendriks, Bert L de Groot, Xiaoying Cai, Changlin Tian, Adam Lange, Han Sun
NaK and other non-selective channels are able to conduct both sodium (Na+ ) and potassium (K+ ) with equally high efficiency. In contrast to previous crystallographic results, we show that the selectivity filter (SF) of NaK in native-like lipid membranes adopts two distinct conformations that are stabilized by either Na+ or K+ ions. The atomic differences of these conformations are resolved by solid-state NMR (ssNMR) spectroscopy and molecular dynamics (MD) simulations. Besides the canonical K+ permeation pathway, we identify a side entry ion-conduction pathway for Na+ permeation unique to NaK...
February 19, 2018: Nature Communications
T J Willis, D G Porter, D J Voneshen, S Uthayakumar, F Demmel, M J Gutmann, M Roger, K Refson, J P Goff
High performance batteries based on the movement of Li ions in Li x CoO 2 have made possible a revolution in mobile electronic technology, from laptops to mobile phones. However, the scarcity of Li and the demand for energy storage for renewables has led to intense interest in Na-ion batteries, including structurally-related Na x CoO 2 . Here we have determined the diffusion mechanism for Na 0.8 CoO 2 using diffuse x-ray scattering, quasi-elastic neutron scattering and ab-initio molecular dynamics simulations, and we find that the sodium ordering provides diffusion pathways and governs the diffusion rate...
February 16, 2018: Scientific Reports
Kevin R DeMarco, Slava Bekker, Colleen E Clancy, Sergei Y Noskov, Igor Vorobyov
Interactions of drug molecules with lipid membranes play crucial role in their accessibility of cellular targets and can be an important predictor of their therapeutic and safety profiles. Very little is known about spatial localization of various drugs in the lipid bilayers, their active form (ionization state) or translocation rates and therefore potency to bind to different sites in membrane proteins. All-atom molecular simulations may help to map drug partitioning kinetics and thermodynamics, thus providing in-depth assessment of drug lipophilicity...
2018: Frontiers in Pharmacology
Fan Zhao, Wei Jin, Lin Ma, Jian-Ye Zhang, Jin-Long Wang, Jing-Hai Zhang, Yong-Bo Song
Voltage-gated sodium (Na v ) channels play a pivotal role for the changes in membrane potential and belong to large membrane proteins that compose four voltage sensor domains (VSD1-4). In this study we describe the binding mode and selectivity of one of the aryl sulfonamide sodium channel inhibitors, PF-04856264, for the VSD4s in Na v 1.4, Na v 1.5 and Na v 1.7, respectively, through molecular dynamics simulation and enhanced post-dynamics analyses. Our results show that there are three binding site regions (BSR1-3) in the combination of the ligand and receptors, of which BSR1 and BSR3 contribute to the selectivity and affinity of the ligand to the receptor...
February 15, 2018: Journal of Biomolecular Structure & Dynamics
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