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Molecular dynamics simulation channel

Parth Rakesh Desai, Shayandev Sinha, Siddhartha Das
We employ molecular dynamics (MD) simulations and develop scaling theories to quantify the equilibrium behavior of polyelectrolyte (PE) brush bilayers (BBLs) in the weakly interpenetrated regime, which is characterized by d_{0}<d_{g}<2d_{0}, where d_{g} is the gap between the opposing plates where the PE brushes are grafted and d_{0} is the unperturbed height of a PE brush grafted at a single plate. Scaling predictions establish that, for the weakly interpenetrated osmotic PE BBLs δ∼N^{1/2}(2-d_{g}/d_{0})^{1/2} (where δ is the interpenetration length and N is the number of Kuhn segments in PE brush)...
March 2018: Physical Review. E
Jagannath Mondal, Navjeet Ahalawat, Subhendu Pandit, Lewis E Kay, Pramodh Vallurupalli
Ligand binding sites in proteins are often localized to deeply buried cavities, inaccessible to bulk solvent. Yet, in many cases binding of cognate ligands occurs rapidly. An intriguing system is presented by the L99A cavity mutant of T4 Lysozyme (T4L L99A) that rapidly binds benzene (~106 M-1s-1). Although the protein has long served as a model system for protein thermodynamics and crystal structures of both free and benzene-bound T4L L99A are available, the kinetic pathways by which benzene reaches its solvent-inaccessible binding cavity remain elusive...
May 18, 2018: PLoS Computational Biology
Takuya Mabuchi, Takashi Tokumasu
A reactive molecular dynamics simulation has been performed for the characterization of the relationship between proton transport and water clustering in polymer electrolyte membranes. We have demonstrated that the anharmonic two-state empirical valence bond ( aTS-EVB) model is capable of describing efficiently excess proton transport through the Grotthuss hopping mechanism within the simplicity of the theoretical framework. In order to explore the long-time diffusion behavior in PFSA membranes with statistical certainty, simulations that are longer than 10 ns are needed...
May 18, 2018: Journal of Physical Chemistry. B
Fatemeh Ebrahimi, Farzaneh Ramazani, Muhammad Sahimi
We report on the results of extensive molecular dynamics simulation of water imbibition in carbon nanotubes (CNTs), connected together by converging or diverging nanojunctions in various configurations. The goal of the study is to understand the effect of the nanojunctions on the interface motion, as well as the differences between what we study and water imbibition in microchannels. While the dynamics of water uptake in the entrance CNT is the same as that of imbibition in straight CNTs, with the main source of energy dissipation being the friction at the entrance, water uptake in the exit CNT is more complex due to significant energy loss in the nanojunctions...
May 17, 2018: Scientific Reports
Igor Ariz-Extreme, Jochen S Hub
Approximately 90% of the structures in the Protein Data Bank (PDB) were obtained by X-ray crystallography or electron microscopy. Whereas the overall quality of structure is considered high, thanks to a wide range of tools for structure validation, uncertainties may arise from density maps of small molecules, such as organic ligands, ions or water, which are non-covalently bound to the biomolecules. Even with some experience and chemical intuition, the assignment of such disconnected electron densities is often far from obvious...
2018: PloS One
Emelie Ertan, Viktoriia Savchenko, Nina Ignatova, Vinícius Vaz da Cruz, Rafael C Couto, Sebastian Eckert, Mattis Fondell, Marcus Dantz, Brian Kennedy, Thorsten Schmitt, Annette Pietzsch, Alexander Föhlisch, Faris Gel'mukhanov, Michael Odelius, Victor Kimberg
In this combined theoretical and experimental study we report on an analysis of the resonant inelastic X-ray scattering (RIXS) spectra of gas phase water via the lowest dissociative core-excited state |1s-1O4a11. We focus on the spectral feature near the dissociation limit of the electronic ground state. We show that the narrow atomic-like peak consists of the overlapping contribution from the RIXS channels back to the ground state and to the first valence excited state |1b-114a11 of the molecule. The spectral feature has signatures of ultrafast dissociation (UFD) in the core-excited state, as we show by means of ab initio calculations and time-dependent nuclear wave packet simulations...
May 17, 2018: Physical Chemistry Chemical Physics: PCCP
Daohua Jiang, Tamer M Gamal El-Din, Christopher Ing, Peilong Lu, Régis Pomès, Ning Zheng, William A Catterall
Potassium-sensitive hypokalaemic and normokalaemic periodic paralysis are inherited skeletal muscle diseases characterized by episodes of flaccid muscle weakness1,2 . They are caused by single mutations in positively charged residues ('gating charges') in the S4 transmembrane segment of the voltage sensor of the voltage-gated sodium channel Nav 1.4 or the calcium channel Cav 1.11,2 . Mutations of the outermost gating charges (R1 and R2) cause hypokalaemic periodic paralysis1,2 by creating a pathogenic gating pore in the voltage sensor through which cations leak in the resting state3,4 ...
May 16, 2018: Nature
Ioannis Skarmoutsos, Mohamed Eddaoudi, Guillaume Maurin
Force field based-Molecular dynamics simulations were deployed to systematically explore the dynamics of confined molecules of different shapes and sizes, i.e. linear (CO2 and N2) and spherical (CH4) fluids, in a model small pore system, i.e. the Metal-Organic Framework SIFSIX-2-Cu-i. These computations unveil an unprecedented molecular symmetry dependence of the translational and rotational dynamics of fluids confined in channel-like nanoporous materials. In particular this peculiar behaviour is reflected by the extremely slow decay of the Legendre reorientational correlation functions of even-parity order for the linear fluids which is associated to jump-like orientation flips, while the spherical fluid shows a very fast decay taking place in a sub-picosecond time scale...
May 15, 2018: Journal of Physical Chemistry Letters
Priscilla S-W Yeung, Megumi Yamashita, Christopher E Ing, Régis Pomès, Douglas M Freymann, Murali Prakriya
Store-operated Orai1 channels are activated through a unique inside-out mechanism involving binding of the endoplasmic reticulum Ca2+ sensor STIM1 to cytoplasmic sites on Orai1. Although atomic-level details of Orai structure, including the pore and putative ligand binding domains, are resolved, how the gating signal is communicated to the pore and opens the gate is unknown. To address this issue, we used scanning mutagenesis to identify 15 residues in transmembrane domains (TMs) 1-4 whose perturbation activates Orai1 channels independently of STIM1...
May 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
Maxime Louet, Céline M Labbé, Charline Fagnen, Cassiano M Aono, Paula Homem-de-Mello, Bruno O Villoutreix, Maria A Miteva
Cytochrome P450 2C9 (CYP2C9) metabolizes about 15% of clinically administrated drugs. The allelic variant CYP2C9*30 (A477T) is associated to diminished response to the antihypertensive effects of the prodrug losartan and affected metabolism of other drugs. Here, we investigated molecular mechanisms involved in the functional consequences of this amino-acid substitution. Molecular dynamics (MD) simulations performed for the active species of the enzyme (heme in the Compound I state), in the apo or substrate-bound state, and binding energy analyses gave insights into altered protein structure and dynamics involved in the defective drug metabolism of human CYP2C9...
2018: PloS One
Victor De La Rosa, Ashley L Bennett, Ian Scott Ramsey
The voltage sensor (VS) domain in Hv1 proton channels mediates a voltage-dependent and H+ -selective "aqueous" conductance (GAQ ) that is potently modulated by extracellular Zn2+ Although two conserved His residues are required for Zn2+ effects on GAQ gating, the atomic structure of the Zn2+ coordination site and mechanism by which extracellular Zn2+ stabilizes a closed-state conformation remain unknown. Here we use His mutagenesis to identify residues that increase Zn2+ potency and are therefore likely to participate in first solvation shell interactions with Zn2+ Experimental Zn2+ -mapping data were then used to constrain the structure of a new resting-state Hv1 model (Hv1 F)...
May 9, 2018: Journal of General Physiology
Adam Jurcik, David Bednar, Jan Byska, Sergio M Marques, Katarina Furmanova, Lukas Daniel, Piia Kokkonen, Jan Brezovsky, Ondrej Strnad, Jan Stourac, Antonin Pavelka, Martin Manak, Jiri Damborsky, Barbora Kozlikova
Motivation: Studying the transport paths of ligands, solvents, or ions in transmembrane proteins and proteins with buried binding sites is fundamental to the understanding of their biological function. A detailed analysis of the structural features influencing the transport paths is also important for engineering proteins for biomedical and biotechnological applications. Results: CAVER Analyst 2.0 is a software tool for quantitative analysis and real-time visualization of tunnels and channels in static and dynamic structures...
May 8, 2018: Bioinformatics
Alfonso Trezza, Vittoria Cicaloni, Piera Porciatti, Andrea Langella, Fabio Fusi, Simona Saponara, Ottavia Spiga
Background: ATP-sensitive inward rectifier potassium channels (Kir), are a potassium channel family involved in many physiological processes. KATP dysfunctions are observed in several diseases such as hypoglycaemia, hyperinsulinemia, Prinzmetal angina-like symptoms, cardiovascular diseases. Methods: A broader view of the KATP mechanism is needed in order to operate on their regulation, and in this work we clarify the structure of the Rattus norvegicus ATP-sensitive inward rectifier potassium channel 8 (Kir6...
2018: PeerJ
Fangling Chen, Wenxin Huang, Tao Jiang, Rilei Yu
Voltage-gated sodium (NaV ) channels generate and propagate action potentials in excitable cells, and several NaV subtypes have become important targets for pain management. The &mu;-conotoxins inhibit subtypes of the NaV with varied specificity but often lack of specificity to interested subtypes. Engineering the selectivity of the &mu;-conotoxins presents considerable complexity and challenge, as it involves the optimization of their binding affinities to multiple highly conserved NaV subtypes. In this study, a model of NaV 1...
May 7, 2018: Marine Drugs
Jean-Pierre Changeux
The concept of allosteric interaction was initially proposed to account for the inhibitory feedback mechanism mediated by bacterial regulatory enzymes. In contrast with the classical mechanism of competitive, steric, interaction between ligands for a common site, allosteric interactions take place between topographically distinct sites and are mediated by a discrete and reversible conformational change of the protein. The concept was soon extended to membrane receptors for neurotransmitters and shown to apply to the signal transduction process which, in the case of the acetylcholine nicotinic receptor (nAChR), links the ACh binding site to the ion channel...
June 19, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
Simone Furini, Carmen Domene
Since the availability of the first crystal structure of a bacterial Na+ channel in 2011, understanding selectivity across this family of membrane proteins has been the subject of intense research efforts. Initially, free energy calculations based on molecular dynamics simulations revealed that although sodium ions can easily permeate the channel with their first hydration shell almost intact, the selectivity filter is too narrow for efficient conduction of hydrated potassium ions. This steric view of selectivity was subsequently questioned by microsecond atomic trajectories, which proved that the selectivity filter appears to the permeating ions as a highly degenerate, liquid-like environment...
May 7, 2018: Proceedings of the National Academy of Sciences of the United States of America
Sajjad Ahmad, Afifa Navid, Amina Saleem Akhtar, Syed Sikander Azam, Abdul Wadood, Horacio Pérez-Sánchez
The emergence and dissemination of pan drug resistant clones of Klebsiella pneumoniae are great threat to public health. In this regard new therapeutic targets must be highlighted to pave the path for novel drug discovery and development. Subtractive proteomic pipeline brought forth UDP-3-O-[3-hydroxymyristoyl] N-acetylglucosamine deacetylase (LpxC), a Zn+2 dependent cytoplasmic metalloprotein and catalyze the rate limiting deacetylation step of lipid A biosynthesis pathway. Primary sequence analysis followed by 3-dimensional (3-D) structure elucidation of the protein led to the detection of K...
May 2, 2018: Interdisciplinary Sciences, Computational Life Sciences
Leonard P Heinz, Wojciech Kopec, Bert L de Groot, Rainer H A Fink
The ryanodine receptor 1 is a large calcium ion channel found in mammalian skeletal muscle. The ion channel gained a lot of attention recently, after multiple independent authors published near-atomic cryo electron microscopy data. Taking advantage of the unprecedented quality of structural data, we performed molecular dynamics simulations on the entire ion channel as well as on a reduced model. We calculated potentials of mean force for Ba2+ , Ca2+ , Mg2+ , K+ , Na+ and Cl- ions using umbrella sampling to identify the key residues involved in ion permeation...
May 2, 2018: Scientific Reports
Elias Christoforides, Andreas Papaioannou, Kostas Bethanis
The role of beta-cyclodextrin (β-CD) in cholesterol removal primarily from mammalian cells and secondly from dairy products has been studied thoroughly in recent years. Although the physicochemical characterization of the inclusion compound of cholesterol in β-CD has been achieved by various methods, no crystal structure has been determined so far. We report here the crystal structure of the inclusion compound of cholesterol in β-CD. The inclusion complex crystallizes in the triclinic space group P 1 forming head-to-head dimers which are stacked along the c -axis...
2018: Beilstein Journal of Organic Chemistry
Lautaro D Alvarez, Adali Pecci
Neurosteroids are the principal endogenous modulators of the γ-Aminobutyric acid receptors (GABAA Rs), pentameric membrane-bound proteins that can be assembled from at least 19 subunits. In the most abundant GABAA R arrangement (α1 β2 γ2 ), neurosteroids can potentiate the GABA action as well as produce a direct activation of the channel. The recent crystal structures of neurosteroids bound to α homopentameric GABAA R reveal binding to five equivalent sites. However, these results have been obtained using receptors that are not physiologically relevant, suggesting a need to investigate neurosteroid binding to heteropentameric receptors that exist in the central nervous system...
April 26, 2018: Journal of Steroid Biochemistry and Molecular Biology
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