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Molecular dynamics simulation channel

Yanmei Hu, Rami Musharrafieh, Chunlong Ma, Jiantao Zhang, Donald F Smee, William F DeGrado, Jun Wang
Adamantanes such as amantadine (1) and rimantadine (2) are FDA-approved anti-influenza drugs that act by inhibiting the wild-type M2 proton channel from influenza A viruses, thereby inhibiting the uncoating of the virus. Although adamantanes have been successfully used for more than four decades, their efficacy was curtailed by emerging drug resistance. Among the limited number of M2 mutants that confer amantadine resistance, the M2-V27A mutant was found to be the predominant mutant under drug selection pressure, thereby representing a high profile antiviral drug target...
January 10, 2017: Antiviral Research
Amy J Glenwright, Karunakar R Pothula, Satya P Bhamidimarri, Dror S Chorev, Arnaud Baslé, Susan J Firbank, Hongjun Zheng, Carol V Robinson, Mathias Winterhalter, Ulrich Kleinekathöfer, David N Bolam, Bert van den Berg
The human large intestine is populated by a high density of microorganisms, collectively termed the colonic microbiota, which has an important role in human health and nutrition. The survival of microbiota members from the dominant Gram-negative phylum Bacteroidetes depends on their ability to degrade dietary glycans that cannot be metabolized by the host. The genes encoding proteins involved in the degradation of specific glycans are organized into co-regulated polysaccharide utilization loci, with the archetypal locus sus (for starch utilisation system) encoding seven proteins, SusA-SusG...
January 11, 2017: Nature
Radhakrishnan Gnanasambandam, Chiranjib Ghatak, Anthony Yasmann, Kazuhisa Nishizawa, Frederick Sachs, Alexey S Ladokhin, Sergei I Sukharev, Thomas M Suchyna
GsMTx4 is a spider venom peptide that inhibits cationic mechanosensitive channels (MSCs). It has six lysine residues that have been proposed to affect membrane binding. We synthesized six analogs with single lysine-to-glutamate substitutions and tested them against Piezo1 channels in outside-out patches and independently measured lipid binding. Four analogs had ∼20% lower efficacy than the wild-type (WT) peptide. The equilibrium constants calculated from the rates of inhibition and washout did not correlate with the changes in inhibition...
January 10, 2017: Biophysical Journal
Mona L Wood, J Alfredo Freites, Francesco Tombola, Douglas J Tobias
Voltage-sensing domains (VSDs) are modular membrane protein units that sense changes in the membrane electrostatic potential, and through conformational changes, regulate a specific function. The VSDs of voltage-dependent K+, Na+, and Ca2+ channels do not conduct ions under physiological conditions, but they can become ion-permeable under pathological conditions through mutations in the voltage sensor, particularly of basic residues (mostly arginines) in the S4 helix. Relatively little is known about the underlying mechanisms of conduction through VSDs...
January 11, 2017: Journal of Physical Chemistry. B
David Butcher, Sophie Bernad, Valerie Derrien, Pierre Sebban, Jaroslava Miksovska
Type 1 nonsymbiotic hemoglobins are found in a wide variety of land plants and exhibit very high affinities for exogenous gaseous ligands. These proteins are presumed to have a role in protecting plant cells from oxidative stress under etiolated/hypoxic conditions through NO dioxygenase activity. In this study we have employed photoacoustic calorimetry, time-resolved absorption spectroscopy, and classical molecular dynamics simulations in order to elucidate thermodynamics, kinetics, and ligand migration pathways upon CO photodissociation from WT and a H73L mutant of type 1 nonsymbiotic hemoglobin from Oryza sativa (rice)...
January 10, 2017: Journal of Physical Chemistry. B
Matteo De March, Nekane Merino, Susana Barrera-Vilarmau, Ramon Crehuet, Silvia Onesti, Francisco J Blanco, Alfredo De Biasio
Sliding clamps encircle DNA and tether polymerases and other factors to the genomic template. However, the molecular mechanism of clamp sliding on DNA is unknown. Using crystallography, NMR and molecular dynamics simulations, here we show that the human clamp PCNA recognizes DNA through a double patch of basic residues within the ring channel, arranged in a right-hand spiral that matches the pitch of B-DNA. We propose that PCNA slides by tracking the DNA backbone via a 'cogwheel' mechanism based on short-lived polar interactions, which keep the orientation of the clamp invariant relative to DNA...
January 10, 2017: Nature Communications
Vanessa J Bukas, Karsten Reuter
We augment ab initio molecular dynamics simulations with a quantitative account of phononic dissipation to study the non-equilibrium aftermath of the exothermic oxygen dissociation at low-index (111), (100), and (110) Pd surfaces. Comparing the hyperthermal diffusion arising from a non-instantaneous dissipation of the released chemical energy, we find a striking difference in the resulting "hot" adatom lifetime that is not overall reflected in experimentally recorded product end distances. We rationalize this finding through a detailed mode-specific phonon analysis and identify the dominant dissipation channels as qualitatively different groups of localized surface modes that ultimately lead to intrinsically different rates of dissipation to the Pd bulk...
January 7, 2017: Journal of Chemical Physics
Otoniel Denis-Alpizar, Raymond J Bemish, Markus Meuwly
The NO(X(2)Π) + N((4)S) reaction which occurs entirely in the triplet manifold of N2O is investigated using quasiclassical trajectories and quantum simulations. Fully-dimensional potential energy surfaces for the (3)A' and (3)A'' states are computed at the MRCI+Q level of theory and are represented using a reproducing kernel Hilbert space. The N-exchange and N2-formation channels are followed by using the multi-state adiabatic reactive molecular dynamics method. Up to 5000 K these reactions occur predominantly on the N2O (3)A'' surface...
January 6, 2017: Physical Chemistry Chemical Physics: PCCP
Yuanying Li, Fengyi Liu, Bin Wang, Qingqing Su, Wenliang Wang, Keiji Morokuma
We report the light-driven isomerization mechanism of a fluorene-based light-driven rotary motor (corresponding to Feringa's 2nd generation rotary motor, [M. M. Pollard et al., Org. Biomol. Chem. 6, 507-512 (2008)]) at the complete active space self-consistent field (CASSCF) and spin-flip time-dependent density functional theory (TDDFT) (SFDFT) levels, combined with the complete active space second-order perturbation theory (CASPT2) single-point energy corrections. The good consistence between the SFDFT and CASSCF results confirms the capability of SFDFT in investigating the photoisomerization step of the light-driven molecular rotary motor, and proposes the CASPT2//SFDFT as a promising and effective approach in exploring photochemical processes...
December 28, 2016: Journal of Chemical Physics
Longtao Han, Predrag Krstić
We find a possible channel for direct nanosynthesis of boron-nitride (BN) nanostructures, including growth of BN nanotubes from a mixture of BN diatomic molecules by quantum-classical molecular dynamics simulations. No catalyst or boron nanoparticle is needed for this synthesis, however the conditions for the synthesis of each of the nanostructures, such as temperature and flux of the BN feedstock are identified and are compatible with the conditions in an electric arc at high pressure. We also find that BN nanostructures can be synthetized by feeding a boron nanoparticle by BN diatomic molecules, however if hydrogen rich molecules like NH3 or HBNH are used as a feedstock, two-dimensional nanoflake stable structures are formed...
January 3, 2017: Nanotechnology
Fan Yang, Jie Zheng
Capsaicin in chili peppers bestows the sensation of spiciness. Since the discovery of its receptor, transient receptor potential vanilloid 1 (TRPV1) ion channel, how capsaicin activates this channel has been under extensive investigation using a variety of experimental techniques including mutagenesis, patch-clamp recording, crystallography, cryo-electron microscopy, computational docking and molecular dynamic simulation. A framework of how capsaicin binds and activates TRPV1 has started to merge: capsaicin binds to a pocket formed by the channel's transmembrane segments, where it takes a "tail-up, head-down" configuration...
January 2, 2017: Protein & Cell
Wen Li, Youguo Yan, Muhan Wang, Petr Král, Caili Dai, Jun Zhang
Using molecular dynamics simulations, we reveal ion rectification in charged nanocones with exit diameters of 1-2 nm. The simulations exhibit an opposite rectification current direction than experiments performed in conical channels with exit diameters larger than 5 nm. This can be understood by the fact that in ultranarrow charged cones screening ions are trapped close to the cone tip at both field directions, which necessitates them to be released from the cone in a correlated multi-ion fashion. Electroosmosis induced by a unidirectional ion flow is also observed...
January 5, 2017: Journal of Physical Chemistry Letters
Francesco Pisani, Laura Simone, Concetta Domenica Gargano, Manuela De Bellis, Antonio Cibelli, Maria Grazia Mola, Giacomo Catacchio, Antonio Frigeri, Maria Svelto, Grazia Paola Nicchia
Aquaporin-4 (AQP4) is the CNS water channel organized into well-ordered protein aggregates called Orthogonal Arrays of Particles (OAPs). Neuromyelitis Optica (NMO) is an autoimmune disease caused by anti-OAP autoantibodies (AQP4-IgG). Molecular Dynamics (MD) simulations have identified an H-bond between L53 and T56 as the key for AQP4 epitope and therefore of potential interest for drug design in NMO field. In the present study, we have experimentally tested this MD-prediction using the classic mutagenesis approach...
December 24, 2016: Biochimica et Biophysica Acta
Chie Funatogawa, Yang Li, Ying Chen, William McDonald, Istvan Szundi, James A Fee, C David Stout, Ólöf Einarsdóttir
Knowledge of the role of conserved residues in the ligand channel of heme-copper oxidases is critical for understanding how the protein scaffold modulates the function of these enzymes. In this study, we investigated the role of the conserved valine 236 in the ligand channel of ba3 cytochrome c oxidase from Thermus thermophilus by mutating the residue to a more polar (V236T), smaller (V236A), or larger (V236I, V236N, V236L, V236M, and V236F) residue. The crystal structures of the mutants were determined, and the effects of the mutations on the rates of CO, O2, and NO binding were investigated...
December 27, 2016: Biochemistry
Marcin Bednarz, Bas C Stunnenberg, Benno Kusters, Erik-Jan Kamsteeg, Christiaan G Saris, James Groome, Vern Winston, Giovanni Meola, Karin Jurkat-Rott, Nicol C Voermans
In sodium channelopathies, a severe fixed myopathy caused by a dominant mutation is rare. We describe two unrelated patients with a novel variant, p.Ile1455Thr, with phenotypes of paramyotonia in one case and fixed proximal myopathy with latent myotonia in another. In-vitro whole cell patch-clamp studies show that the mutation slows inactivation and accelerates recovery, in line with other paramyotonia variants with destabilized fast inactivation as pathomechanism. Additionally, p.IleI1455 causes a loss-of-function by reduced membrane insertion, right-shift of activation, and slowed kinetics...
October 19, 2016: Neuromuscular Disorders: NMD
Carlo Guardiani, P Mark Rodger, Igor A Khovanov
NaChBac was the first discovered sodium voltage dependent channel, yet computational studies are still limited due to the lack of a crystal structure. In this work a pore-only construct built using the NavMs template was investigated using unbiased Molecular Dynamics and Metadynamics. The Potential of Mean Force (PMF) from the unbiased run features four minima, three of which correspond to sites IN, CEN and HFS discovered in NavAb. During the run the Selectivity Filter (SF) is spontaneously occupied by two ions and frequent access of a third one is often observed...
December 26, 2016: Journal of Chemical Theory and Computation
Steven E Strong, Joel D Eaves
Porous two-dimensional crystals offer many promises for water desalination applications. For computer simulation to play a predictive role in this area, however, one needs to have reliable methods for simulating an atomistic system with hydrodynamic currents and interpretative tools to relate microscopic interactions to emergent macroscopic dynamical quantities, such as friction, slip length, and permeability. In this article, we use Gaussian dynamics, a nonequilibrium molecular dynamics method that provides microscopic insights into the interactions that control the flows of both simple liquids and liquid water through atomically small channels...
December 23, 2016: Journal of Physical Chemistry. B
Gustavo Pierdominici-Sottile, Luciano Moffatt, Juliana Palma
We present the results of a detailed molecular dynamics study of the closed form of the P2X4 receptor. The fluctuations observed in the simulations were compared with the changes that occur in the transition from the closed to the open structure. To get further insight on the opening mechanism, the actual displacements were decomposed into interchain motions and intrachain deformations. This analysis revealed that the iris-like expansion of the transmembrane helices mainly results from interchain motions that already take place in the closed conformation...
December 20, 2016: Biophysical Journal
Margarita Monastyrnaya, Steve Peigneur, Elena Zelepuga, Oksana Sintsova, Irina Gladkikh, Elena Leychenko, Marina Isaeva, Jan Tytgat, Emma Kozlovskaya
Sea anemone venoms comprise multifarious peptides modulating biological targets such as ion channels or receptors. The sequence of a new Kunitz-type peptide, HCRG21, belonging to the Heteractis crispa RG (HCRG) peptide subfamily was deduced on the basis of the gene sequence obtained from the Heteractis crispa cDNA. HCRG21 shares high structural homology with Kunitz-type peptides APHC1-APHC3 from H. crispa, and clusters with the peptides from so named "analgesic cluster" of the HCGS peptide subfamily but forms a separate branch on the NJ-phylogenetic tree...
December 15, 2016: Marine Drugs
Dhani Ram Mahato, Wolfgang B Fischer
Protein E5 is a polytopic 83 amino acid membrane protein with three transmembrane domains (TMDs), encoded by high-risk human papillomavirus-16 (HPV-16). HPV-16 is found to be the causative agent for cervical cancer. Protein E5, among other proteins (e.g., E6, E7), is expressed at an "early" (E) stage when the cell turns malignant. It has been experimentally found that E5 forms hexameric assemblies, which show the characteristics of the class of so-called channel-forming proteins by rendering lipid membranes permeable to ions and small molecules...
December 29, 2016: Journal of Physical Chemistry. B
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