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Molecular dynamics simulation channel

Jingwei Zhou, Yue Huang, Chunyan Cheng, Kai Wang, Ruibo Wu
The development of novel isoform/class-selective inhibitor is still of great biological and medical significance to conquer the continuously reported side effects for the histone deacetylases (HDACs) drugs. The first potent HDAC allosteric inhibitor was discovered last year and this allosteric inhibitor design is thought to be a promising strategy to overcome the current challenges in HDAC inhibitor design. However, the detailed allosteric mechanisms and its remote regulation effects on the catalytic/inhibitor activity of HDAC are still unclear...
August 14, 2017: Journal of Chemical Information and Modeling
Tamal Roy, Kai Szuttor, Jens Smiatek, Christian Holm, Steffen Hardt
We study the effect of pressure-driven flow on a single surface-tethered DNA molecule confined between parallel surfaces. The influence of flow and channel parameters as well as the length of the molecules on their extension and orientation is explored. In the experiments the chain conformations are imaged by laser scanning confocal microscopy. We find that the fractional extension of the tethered DNA molecules mainly depends on the wall shear stress, with effects of confinement being very weak. Experiments performed with molecules of different contour length show that the fractional extension is a universal function of the product of the wall shear stress and the contour length, a result that can be obtained from a simple scaling relation...
August 11, 2017: Soft Matter
Outi Haapanen, Vivek Sharma
Membrane bound respiratory complex I is the key enzyme in the respiratory chains of bacteria and mitochondria, and couples the reduction of quinone to the pumping of protons across the membrane. Recently solved crystal or electron microscopy structures of bacterial and mitochondrial complexes have provided significant insights into the electron and proton transfer pathways. However, due to large spatial separation between the electron and proton transfer routes, the molecular mechanism of coupling remains unclear...
August 10, 2017: Scientific Reports
Bogdan F Ion, Marta M Wells, Qiang Chen, Yan Xu, Pei Tang
Ketamine inhibits pentameric ligand-gated ion channels (pLGICs), including the bacterial pLGIC from Gloeobacter violaceus (GLIC). The crystal structure of GLIC shows R-ketamine bound to an extracellular intersubunit cavity. Here, we performed molecular dynamics simulations of GLIC in the absence and presence of R- or S-ketamine. No stable binding of S-ketamine in the original cavity was observed in the simulations, largely due to its unfavorable access to residue D154, which provides important electrostatic interactions to stabilize R-ketamine binding...
August 8, 2017: Biophysical Journal
Oleg G Deryagin, Svetlana A Gavrilova, Khalil L Gainutdinov, Anna V Golubeva, Vyatcheslav V Andrianov, Guzel G Yafarova, Sergey V Buravkov, Vladimir B Koshelev
Preconditioning of the brain induces tolerance to the damaging effects of ischemia and prevents cell death in ischemic penumbra. The development of this phenomenon is mediated by mitochondrial adenosine triphosphate-sensitive potassium ([Formula: see text]) channels and nitric oxide signaling (NO). The aim of this study was to investigate the dynamics of molecular changes in mitochondria after ischemic preconditioning (IP) and the effect of pharmacological preconditioning (PhP) with the [Formula: see text]-channels opener diazoxide on NO levels after ischemic stroke in rats...
2017: Frontiers in Neuroscience
Anna Rita Bizzarri, Chiara Baldacchini, Salvatore Cannistraro
Blue copper redox protein Azurin (AZ) constitutes an ideal active element for building bio-nano-optoelectronic devices based on the intriguing interplay among its electron transfer (ET), vibrational and optical properties. A full comprehension of its dynamical and functional behaviour is required for efficient applications. Here, AZ bound to gold electrode via its disulphide bridge was investigated by a Molecular Dynamics simulation approach taking into account for gold electron polarization which provides a more realistic description of the protein-gold interaction...
August 9, 2017: Langmuir: the ACS Journal of Surfaces and Colloids
Veronika Navrátilová, Markéta Paloncýová, Karel Berka, Shintaro Mise, Yuki Haga, Chisato Matsumura, Toshiyuki Sakaki, Hideyuki Inui, Michal Otyepka
BACKGROUND: Cytochromes P450 are major drug-metabolizing enzymes involved in the biotransformation of diverse xenobiotics and endogenous chemicals. Persistent organic pollutants (POPs) are toxic hydrophobic compounds that cause serious environmental problems because of their poor degradability. This calls for rational design of enzymes capable of catalyzing their biotransformation. Cytochrome P450 1A1 isoforms catalyze the biotransformation of some POPs, and constitute good starting points for the design of biocatalysts with tailored substrate specificity...
August 2, 2017: Biochimica et Biophysica Acta
Hedvig Tordai, Ibolya Leveles, Tamás Hegedűs
Cystic fibrosis (CF), a lethal monogenic disease, is caused by mutant variants of the CF transmembrane conductance regulator (CFTR). Recent advances in single molecule cryo-EM methods enabled structural determination of full-length human and zebrafish CFTR, achieving an important milestone for CF drug development. To relate these structures to the gating cycle, we examined its dynamic features using molecular dynamics simulations. Our results show that the nucleotide binding domains (NBDs) in this bottom-open apo conformation exhibit motions related to dimerization and the bottom-closed apo CFTR model indicates opening of NBDs in contrast to transporters...
July 31, 2017: Biochemical and Biophysical Research Communications
Manuel Radek, Bartosz Liedke, Bernd Schmidt, Matthias Voelskow, Lothar Bischoff, John Lundsgaard Hansen, Arne Nylandsted Larsen, Dominique Bougeard, Roman Böttger, Slawomir Prucnal, Matthias Posselt, Hartmut Bracht
Crystalline and preamorphized isotope multilayers are utilized to investigate the dependence of ion beam mixing in silicon (Si), germanium (Ge), and silicon germanium (SiGe) on the atomic structure of the sample, temperature, ion flux, and electrical doping by the implanted ions. The magnitude of mixing is determined by secondary ion mass spectrometry. Rutherford backscattering spectrometry in channeling geometry, Raman spectroscopy, and transmission electron microscopy provide information about the structural state after ion irradiation...
July 17, 2017: Materials
Hui Yu, Lianjuan Yang, Lu Liu, Xi Zhao, Xuri Huang
Acid-sensing ion channel 1a (ASIC1a) is a cation channel activated by protons and causes neuronal death through central nervous system. Psalmotoxin1 (PcTx1) is a gating modifier for ASIC1a. The process of PcTx1 regulating the channel gating from the extracellular domain to the transmembrane domain is unclear. Here we used molecular dynamics (MD) simulations method to investigate how PcTx1 regulates the gating of the ASIC1a. Our results indicated that PcTx1can mainly regulate ASIC1a gating process through hydrogen bonds, which can affect their relative positions of several key domains in ASIC1a, further, a long-range conformational changes path was determined, which is composed of β1, β2, β10, α6, α7, β11 and β12 in ASIC1a...
August 3, 2017: Journal of Biomolecular Structure & Dynamics
Subin Sahu, Michael Zwolak
Selective ion transport is a hallmark of biological ion channel behavior but is a major challenge to engineer into artificial membranes. Here, we demonstrate, with all-atom molecular dynamics simulations, that bare graphene nanopores yield measurable ion selectivity that varies over one to two orders of magnitude simply by changing the pore radius and number of graphene layers. Monolayer graphene does not display dehydration-induced selectivity until the pore radius is small enough to exclude the first hydration layer from inside the pore...
August 2, 2017: Nanoscale
Luming Meng, Fu Kit Sheong, Xiangze Zeng, Lizhe Zhu, Xuhui Huang
Constructing Markov state models from large-scale molecular dynamics simulation trajectories is a promising approach to dissect the kinetic mechanisms of complex chemical and biological processes. Combined with transition path theory, Markov state models can be applied to identify all pathways connecting any conformational states of interest. However, the identified pathways can be too complex to comprehend, especially for multi-body processes where numerous parallel pathways with comparable flux probability often coexist...
July 28, 2017: Journal of Chemical Physics
Maria A Principalli, Laura Lemel, Anaëlle Rongier, Anne-Claire Godet, Karla Langer, Jean Revilloud, Leonardo Darré, Carmen Domene, Michel Vivaudou, Christophe J Moreau
Ion channel-coupled receptors (ICCRs) are original man-made ligand-gated ion channels created by fusion of G protein-coupled receptors (GPCRs) to the inward-rectifier potassium channel Kir6.2. GPCR conformational changes induced by ligand binding are transduced into electrical current by the ion channel. This functional coupling is closely related to the length of the linker region formed by the GPCR C-terminus (C-ter) and Kir6.2N-terminus (N-ter). Manipulating the GPCR C-ter length allows to finely tune the channel regulation, both in amplitude and sign (opening or closing Kir6...
July 27, 2017: Biochimica et Biophysica Acta
Samuel Murail
Membrane proteins are involved in a large variety of functions. Most of these protein functions are regulated by ligand binding with diverse modes of action: agonists, partial agonists, antagonists, and allosteric modulators, potentiators and inhibitors. From the pharmacological point of view, membrane proteins are one if not the major target for drug development. However, experimental structure determination of membrane proteins in complex or in free form still represents a great challenge. Molecular dynamics (MD) simulations commonly reach the microsecond scale on membrane systems...
2017: Methods in Molecular Biology
Juan Du, Xiaolu Wang, Qingjuan Nie, Jianming Yang, Xiaojun Yao
The acyl-AMP forming family of adenylating enzymes catalyzes the formation of acyl-CoA from an acyl substrate, ATP, and CoA, which is a metabolite of many catabolic and anabolic processes. The medium-chain acyl-CoA synthetase from Methanosarcina acetivorans, designated MacsMa, uses 2-methylbutyrate as its preferred substrate. It is reported that the interaction between the sidechain of Cys298 and Lys256 of this enzyme is important for the catalytic activity. The mutation of these residues resulted in the changes of the structure stability and the reduced or absence catalytic activity...
July 24, 2017: Journal of Biotechnology
Karl Decker, Martin Page, Aleksei Aksimentiev
Biological molecular machines perform the work of supporting life at the smallest of scales, including the work of shuttling ions across cell boundaries and against chemical gradients. Systems of artificial channels at the nanoscale can likewise control ionic concentration by way of ionic current rectification, species selectivity, and voltage gating mechanisms. Here, we theoretically show that a voltage-gated, ion species-selective, and rectifying ion channel can be built using the components of a biological water channel aquaporin...
August 9, 2017: Journal of Physical Chemistry. B
Maria Seitanidou, Juan Felipe Franco-Gonzalez, Theresia Arbring Sjöström, Igor Zozoulenko, Magnus Berggren, Daniel T Simon
The organic electronic ion pump (OEIP) has been developed as an "iontronic" tool for delivery of biological signaling compounds. OEIPs rely on electrophoretically "pumping" charged compounds, either at neutral or shifted pH, through an ion-selective channel. Significant shifts in pH lead to an abundance of H(+) or OH(-), which are delivered along with the intended substance. While this method has been used to transport various neurotransmitters, the role of pH has not been explored. Here we present an investigation of the role of pH on OEIP transport efficiency using the neurotransmitter γ-aminobutyric acid (GABA) as the model cationic delivery substance...
July 25, 2017: Journal of Physical Chemistry. B
Xiaodong Pang, Huan-Xiang Zhou
NMDA receptors are tetrameric ligand-gated ion channels that are crucial for neurodevelopment and higher order processes such as learning and memory, and have been implicated in numerous neurological disorders. The lack of a structure for the channel open state has greatly hampered the understanding of the normal gating process and mechanisms of disease-associated mutations. Here we report the structural modeling for the open state of an NMDA receptor. Staring from the crystal structure of the closed state, we repacked the pore-lining helices to generate an initial open model...
July 22, 2017: Journal of Structural Biology
Kai Szuttor, Tamal Roy, Steffen Hardt, Christian Holm, Jens Smiatek
We use mesoscopic lattice-Boltzmann/molecular dynamics simulations to study the stretching behavior of a single tethered polymer in micro- and nanochannels. In particular, we are interested in the connection between fluid flow properties and the force on the polymer chain. An analytical expression for the stretching force is proposed, which linearly depends on the number of monomers and the boundary shear rate. In agreement with theory, the numerical findings reveal that the influence of hydrodynamic interactions can be ignored, which is also supported by results of additional Langevin dynamics simulations...
July 21, 2017: Journal of Chemical Physics
Xian Kong, Zeyu Zhao, Jianwen Jiang
Water channels are essential to life sciences and many biological processes. We report a molecular simulation study on dipeptides embedded in a lipid (dipalmitoylphosphatidylcholine) membrane as synthetic water channels. Five dipeptides are examined including FF, FL, LF, and LL (with hydrophilic channels) and AV (with hydrophobic channel). It is found that AV is unstable in the lipid membrane due to incompatible interaction between the hydrophilic external surface of AV and the hydrophobic lipid tails; whereas FF, FL, LF, and LL with hydrophobic external surface exhibit good stability...
August 4, 2017: Langmuir: the ACS Journal of Surfaces and Colloids
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