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Molecular dynamics simulation channel

Kota Kasahara, Kengo Kinoshita
Ion conduction mechanisms of ion channels are a long-standing conundrum. Although the molecular dynamics (MD) method has been extensively used to simulate ion conduction dynamics at the atomic level, analysis and interpretation of MD results are not straightforward due to complexity of the dynamics. In our previous reports, we proposed an analytical method called ion-binding state analysis to scrutinize and summarize ion conduction mechanisms by taking advantage of a variety of analytical protocols, e.g., the complex network analysis, sequence alignment, and hierarchical clustering...
2016: PloS One
Jemma L Trick, Sivapalan Chelvaniththilan, Gianni Klesse, Prafulla Aryal, E Jayne Wallace, Stephen J Tucker, Mark S P Sansom
Ion channels play key roles in cell membranes, and recent advances are yielding an increasing number of structures. However, their functional relevance is often unclear and better tools are required for their functional annotation. In sub-nanometer pores such as ion channels, hydrophobic gating has been shown to promote dewetting to produce a functionally closed (i.e., non-conductive) state. Using the serotonin receptor (5-HT3R) structure as an example, we demonstrate the use of molecular dynamics to aid the functional annotation of channel structures via simulation of the behavior of water within the pore...
November 8, 2016: Structure
Fayezeh Mofidi Najjar, Rahim Ghadari, Reza Yousefi, Naser Safari, Vahid Sheikhhasani, Nader Sheibani, Ali Akbar Moosavi-Movahedi
Curcumin is an important antioxidant compound, and is widely reported as an effective component for reducing complications of many diseases. However, the detailed mechanisms of its activity remain poorly understood. We found that curcumin can significantly increase catalase activity of BLC (bovine liver catalase). The mechanism of curcumin action was investigated using a computational method. We suggested that curcumin may activate BLC by modifying the bottleneck of its narrow channel. The molecular dynamic simulation data showed that placing curcumin on the structure of enzyme can increase the size of the bottleneck in the narrow channel of BLC, and readily allow the access of substrate to the active site...
November 16, 2016: International Journal of Biological Macromolecules
Theodros Zelleke, Dominik Marx
The rate-determining step in the reductive half-reaction of the bacterial enzyme methylamine dehydrogenase (MADH), which is proton abstraction from the native substrate methylamine, is investigated using accelerated QM/MM molecular dynamics simulations at room temperature. Generation of the multi-dimensional thermal free energy landscape without restricting degrees of freedom beyond a multi-dimensional reaction subspace maps two rather similar pathways underlying proton transfer to either the OD1 or OD2 site...
November 16, 2016: Chemphyschem: a European Journal of Chemical Physics and Physical Chemistry
Marcel P Goldschen-Ohm, Vadim A Klenchin, David S White, John B Cowgill, Qiang Cui, Randall H Goldsmith, Baron Chanda
Although molecular recognition is crucial for cellular signaling, mechanistic studies have relied primarily on ensemble measures that average over and thereby obscure underlying steps. Single-molecule observations that resolve these steps are lacking due to diffraction-limited resolution of single fluorophores at relevant concentrations. Here, we combined zero-mode waveguides with fluorescence resonance energy transfer (FRET) to directly observe binding at individual cyclic nucleotide-binding domains (CNBDs) from human pacemaker ion channels critical for heart and brain function...
November 18, 2016: ELife
Raul Araya-Secchi, Brandon L Neel, Marcos Sotomayor
Tip link filaments convey force and gate inner-ear hair-cell transduction channels to mediate perception of sound and head movements. Cadherin-23 and protocadherin-15 form tip links through a calcium-dependent interaction of their extracellular domains made of multiple extracellular cadherin (EC) repeats. These repeats are structurally similar, but not identical in sequence, often featuring linkers with conserved calcium-binding sites that confer mechanical strength to them. Here we present the X-ray crystal structures of human protocadherin-15 EC8-EC10 and mouse EC9-EC10, which show an EC8-9 canonical-like calcium-binding linker, and an EC9-10 calcium-free linker that alters the linear arrangement of EC repeats...
November 18, 2016: Nature Communications
Jafar Ghorbanian, Alper T Celebi, Ali Beskok
A phenomenological continuum model is developed using systematic molecular dynamics (MD) simulations of force-driven liquid argon flows confined in gold nano-channels at a fixed thermodynamic state. Well known density layering near the walls leads to the definition of an effective channel height and a density deficit parameter. While the former defines the slip-plane, the latter parameter relates channel averaged density with the desired thermodynamic state value. Definitions of these new parameters require a single MD simulation performed for a specific liquid-solid pair at the desired thermodynamic state and used for calibration of model parameters...
November 14, 2016: Journal of Chemical Physics
Robert A Pearlstein, Callum J Dickson, Viktor Hornak
The membrane dipole potential (Ψd) constitutes one of three electrical potentials generated by cell membranes. Ψd arises from the unfavorable parallel alignment of phospholipid and water dipoles, and varies in magnitude both longitudinally and laterally across the bilayer according to membrane composition and phospholipid packing density. In this work, we propose that dynamic counter-balancing between Ψd and the transmembrane potential (ΔΨm) governs the conformational state transitions of voltage-gated ion channels...
November 9, 2016: Biochimica et Biophysica Acta
Ashutosh Srivastava, Somdatta Sinha
Anthranilate synthase (AS) is the first branch node enzyme that catalyzes the conversion of chorismate to anthranilate in the high energy-consuming tryptophan biosynthetic pathway in Serratia marcescens. AS, with an allosterically-bound inhibitor (tryptophan), shows complete inhibition in its catalytic function, but the inhibitor-bound structure is very similar to that of the substrate-bound AS. Even though the reaction mechanisms of several chorismate-utilizing enzymes are known, the unusual structure-function relationship in catalysis and allosteric inhibition of AS by tryptophan, with an insignificant change in structure, remains elusive...
November 11, 2016: Molecular BioSystems
Biplab Ghosh, Venuka Durani Goyal
Histidine is ubiquitous in enzyme active sites but its role is often difficult to ascribe due to ambiguity of protonation state and complex electrostatic and dynamic effects involved. In this study the role of His 72 in TmPurL, a glutamine amidotransferase (GAT) enzyme, is investigated. TmPurL is a large 66kDa enzyme that works as part of an even larger (>100kDa) multi-protein complex. This enzyme complex performs an essential step in the purine biosynthesis pathway by abstracting ammonia from a glutamine molecule and channeling it 30Å away into the active site of TmPurL, incorporating it into a purine biosynthesis intermediate...
October 25, 2016: Bioorganic & Medicinal Chemistry Letters
Gabriela C Araujo, Ricardo H T Silva, Luis P B Scott, Alexandre S Araujo, Fatima P Souza, Ronaldo Junio de Oliveira
The human respiratory syncytial virus (hRSV) is the major cause of lower respiratory tract infection in children and elderly people worldwide. Its genome encodes 11 proteins including SH protein, whose functions are not well known. Studies show that SH protein increases RSV virulence degree and permeability to small compounds, suggesting it is involved in the formation of ion channels. The knowledge of SH structure and function is fundamental for a better understanding of its infection mechanism. The aim of this study was to model, characterize, and analyze the structural behavior of SH protein in the phospholipids bilayer environment...
December 2016: Journal of Molecular Modeling
Nitika Chaudhary, Padmani Sandhu, Mushtaq Ahmed, Yusuf Akhter
Trichothecenes are the sesquiterpenes secreted by Trichoderma spp. residing in the rhizosphere. These compounds have been reported to act as plant growth promoters and bio-control agents. The structural knowledge for the transporter proteins of their efflux remained limited. In this study, three-dimensional structure of Thmfs1 protein, a trichothecene transporter from Trichoderma harzianum, was homology modelled and further Molecular Dynamics(MD) simulations were used to decipher its mechanism. Fourteen transmembrane helices of Thmfs1 protein are observed contributing to an inward-open conformation...
November 2, 2016: International Journal of Biological Macromolecules
Siri Camee van Keulen, Eleonora Gianti, Vincenzo Carnevale, Michael L Klein, Ursula Rothlisberger, Lucie Delemotte
Hv1 are ubiquitous highly selective voltage-gated proton channels involved in male fertility, immunology and the invasiveness of certain forms of breast cancer. The mechanism of proton extrusion in Hv1 is not yet understood while it constitutes the first step towards the design of high-affinity drugs aimed at this important pharmacological target. In this contribution, we explore the details of the mechanism via an integrative approach, using classical and QM/MM molecular dynamics simulations of a monomeric hHv1 model...
November 1, 2016: Journal of Physical Chemistry. B
Jang Ho Ha, Tae Hyeon Kim, Jong Min Lee, Christian D Ahrberg, Bong Geun Chung
We developed a three-dimensional (3D) simple multi-layer microfluidic gradient generator to create molecular gradients on the centimeter scale with a wide range of flow rates. To create the concentration gradients, a main channel (MC) was orthogonally intersected with vertical side microchannel (SC) in a 3D multi-layer microfluidic device. Through sequential dilution from the SC, a spatial gradient was generated in the MC. Two theoretical models were created to assist in the design of the 3D multi-layer microfluidic gradient generator and to compare its performance against a two-dimensional (2D) equivalent...
November 1, 2016: Electrophoresis
Aashish Jain, Julian Sheats, Jeffrey G Reifenberger, Han Cao, Kevin D Dorfman
We have developed a multi-scale model describing the dynamics of internal segments of DNA in nanochannels used for genome mapping. In addition to the channel geometry, the model takes as its inputs the DNA properties in free solution (persistence length, effective width, molecular weight, and segmental hydrodynamic radius) and buffer properties (temperature and viscosity). Using pruned-enriched Rosenbluth simulations of a discrete wormlike chain model with circa 10 base pair resolution and a numerical solution for the hydrodynamic interactions in confinement, we convert these experimentally available inputs into the necessary parameters for a one-dimensional, Rouse-like model of the confined chain...
September 2016: Biomicrofluidics
Siladitya Padhi, U Deva Priyakumar
Human aquaporin 2 (AQP2) from the family of aquaporins assumes great physiological importance, owing to its association with nephrogenic diabetes insipidus (NDI). The present study provides detailed insights into the transport properties of AQP2 with the use of microsecond-scale molecular dynamics simulations, and explains how these channels conduct water molecules while at the same time excluding other molecules. Water transport is seen to be diffusion-limited, with a barrier of only 1.6kcalmol(-1), and the channel is more water-permeable than other known aquaporins...
October 26, 2016: Biochimica et Biophysica Acta
Ruibin Liang, Jessica M J Swanson, Jesper J Madsen, Mei Hong, William F DeGrado, Gregory A Voth
The homotetrameric influenza A M2 channel (AM2) is an acid-activated proton channel responsible for the acidification of the influenza virus interior, an important step in the viral lifecycle. Four histidine residues (His37) in the center of the channel act as a pH sensor and proton selectivity filter. Despite intense study, the pH-dependent activation mechanism of the AM2 channel has to date not been completely understood at a molecular level. Herein we have used multiscale computer simulations to characterize (with explicit proton transport free energy profiles and their associated calculated conductances) the activation mechanism of AM2...
October 24, 2016: Proceedings of the National Academy of Sciences of the United States of America
Thomas Zeuthen, Edurne Gorraitz, Ka Her, Ernest M Wright, Donald D F Loo
Membrane transporters, in addition to their major role as specific carriers for ions and small molecules, can also behave as water channels. However, neither the location of the water pathway in the protein nor their functional importance is known. Here, we map the pathway for water and urea through the intestinal sodium/glucose cotransporter SGLT1. Molecular dynamics simulations using the atomic structure of the bacterial transporter vSGLT suggest that water permeates the same path as Na(+) and sugar. On a structural model of SGLT1, based on the homology structure of vSGLT, we identified and mutated residues lining the sugar transport pathway to cysteine...
November 1, 2016: Proceedings of the National Academy of Sciences of the United States of America
Daniel P Dowling, Yan Kung, Anna K Croft, Koli Taghizadeh, Wendy L Kelly, Christopher T Walsh, Catherine L Drennan
Epothilones are thiazole-containing natural products with anticancer activity that are biosynthesized by polyketide synthase (PKS)-nonribosomal peptide synthetase (NRPS) enzymes EpoA-F. A cyclization domain of EpoB (Cy) assembles the thiazole functionality from an acetyl group and l-cysteine via condensation, cyclization, and dehydration. The PKS carrier protein of EpoA contributes the acetyl moiety, guided by a docking domain, whereas an NRPS EpoB carrier protein contributes l-cysteine. To visualize the structure of a cyclization domain with an accompanying docking domain, we solved a 2...
November 1, 2016: Proceedings of the National Academy of Sciences of the United States of America
Mieke Nys, Eveline Wijckmans, Ana Farinha, Özge Yoluk, Magnus Andersson, Marijke Brams, Radovan Spurny, Steve Peigneur, Jan Tytgat, Erik Lindahl, Chris Ulens
Pentameric ligand-gated ion channels or Cys-loop receptors are responsible for fast inhibitory or excitatory synaptic transmission. The antipsychotic compound chlorpromazine is a widely used tool to probe the ion channel pore of the nicotinic acetylcholine receptor, which is a prototypical Cys-loop receptor. In this study, we determine the molecular determinants of chlorpromazine binding in the Erwinia ligand-gated ion channel (ELIC). We report the X-ray crystal structures of ELIC in complex with chlorpromazine or its brominated derivative bromopromazine...
October 25, 2016: Proceedings of the National Academy of Sciences of the United States of America
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