scholarly journals Unexpected Gating Behaviour of an Engineered Potassium Channel Kir

2021 ◽  
Vol 8 ◽  
Author(s):  
Charline Fagnen ◽  
Ludovic Bannwarth ◽  
Dania Zuniga ◽  
Iman Oubella ◽  
Rita De Zorzi ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Normal Modes ◽  
Restriction Point ◽  
Dynamical Characteristics ◽  
Open Conformation ◽  
In The Wild ◽  
Dynamics Simulations ◽  
Hdx Ms ◽  
Global And Local ◽  
Pore Lining

In this study, we investigated the dynamics and functional characteristics of the KirBac3.1 S129R, a mutated bacterial potassium channel for which the inner pore-lining helix (TM2) was engineered so that the bundle crossing is trapped in an open conformation. The structure of this channel has been previously determined at high atomic resolution. We explored the dynamical characteristics of this open state channel using an in silico method MDeNM that combines molecular dynamics simulations and normal modes. We captured the global and local motions at the mutation level and compared these data with HDX-MS experiments. MDeNM provided also an estimation of the probability of the different opening states that are in agreement with our electrophysiological experiments. In the S129R mutant, the Arg129 mutation releases the two constriction points in the channel that existed in the wild type but interestingly creates another restriction point.

How to Fluorescently Label the Potassium Channel: A Case in hERG

2020 ◽  
Vol 27 (18) ◽  
pp. 3046-3054
Author(s):  
Xiaomeng Zhang ◽  
Beilei Wang ◽  
Zhenzhen Liu ◽  
Yubin Zhou ◽  
Lupei Du
Keyword(s):  
Potassium Channel ◽  
Herg Channel ◽  
Pore Channel ◽  
Design Rationale ◽  
Related Gene ◽  
Open Conformation ◽  
Cardiac Action ◽  
Qt Syndrome ◽  
Herg Channels ◽  
Action Potential Repolarization

hERG (Human ether-a-go-go-related gene) potassium channel, which plays an essential role in cardiac action potential repolarization, is responsible for inherited and druginduced long QT syndrome. Recently, the Cryo-EM structure capturing the open conformation of hERG channel was determined, thus pushing the study on hERG channel at 3.8 Å resolution. This report focuses primarily on summarizing the design rationale and application of several fluorescent probes that target hERG channels, which enables dynamic and real-time monitoring of potassium pore channel affinity to further advance the understanding of the channels.

Discrete breathers modeling from first principles in graphene and in classical approximation in fcc Ni: Comparison

2019 ◽  
Vol 04 (02) ◽  
pp. 1950002 ◽  
Author(s):  
Ivan P. Lobzenko
Keyword(s):  
Molecular Dynamics ◽  
First Principles ◽  
High Frequency ◽  
Normal Modes ◽  
Nonlinear Normal Modes ◽  
First Principles Calculations ◽  
Discrete Breathers ◽  
Points Of View ◽  
Nonlinear Normal ◽  
Dynamics Simulations

Properties of discrete breathers are discussed from two points of view: (I) the ab initio modeling in graphene and (II) classical molecular dynamics simulations in the ace-centered cubic (fcc) Ni. In the first (I) approach, the possibility of exciting breathers depends on the strain applied to the graphene sheet. The uniaxial strain leads to opening the gap in the phonon band and, therefore, the existence of breathers with frequencies within the gap. In the second (II) approach, the structure of fcc Ni supports breathers of another kind, which possess a hard nonlinearity type. It is shown that particular high frequency normal mode can be used to construct the breather by means of overlaying a spherically symmetrical function, the maximum of which coincides with the breather core. The approach of breathers excitation based on nonlinear normal modes is independent of the level of approximation. Even though breathers could be obtained both in classical and first-principles calculations, each case has advantages and shortcomings, that are compared in the present work.

scholarly journals In Silico and In Cell Analysis of Openable DNA Nanocages for miRNA Silencing

2019 ◽  
Vol 21 (1) ◽  
pp. 61
Author(s):  
Sofia Raniolo ◽  
Federico Iacovelli ◽  
Valeria Unida ◽  
Alessandro Desideri ◽  
Silvia Biocca
Keyword(s):  
Gel Electrophoresis ◽  
High Stability ◽  
Integrated Approach ◽  
Bond Number ◽  
Cell Analysis ◽  
Stable Conformation ◽  
Dna Hairpins ◽  
Open Conformation ◽  
Internal Volume ◽  
Dynamics Simulations

A computational and experimental integrated approach was applied in order to study the effect of engineering four DNA hairpins into an octahedral truncated DNA nanocage, to obtain a nanostructure able to recognize and bind specific oligonucleotide sequences. Modeling and classical molecular dynamics simulations show that the new H4-DNA nanocage maintains a stable conformation with the closed hairpins and, when bound to complementary oligonucleotides produces an opened conformation that is even more stable due to the larger hydrogen bond number between the hairpins and the oligonucleotides. The internal volume of the open conformation is much larger than the closed one, switching from 370 to 650 nm3, and the predicted larger conformational change is experimentally detectable by gel electrophoresis. H4-DNA nanocages display high stability in serum, can efficiently enter the cells where they are stable and maintain the ability to bind, and sequester an intracellular-specific oligonucleotide. Moreover, H4-DNA nanocages, modified in order to recognize the oncogenic miR21, are able to seize miRNA molecules inside cells in a selective manner.

Analysis of Heat Conduction in Silicon Using Molecular Dynamics Simulations

2006 ◽  
Author(s):  
Asegun S. Henry ◽  
Gang Chen
Keyword(s):  
Molecular Dynamics ◽  
Lattice Dynamics ◽  
Crystalline Silicon ◽  
Relaxation Times ◽  
Normal Modes ◽  
Md Simulations ◽  
Dynamics Simulations ◽  
Technological Significance ◽  
Fitting Parameters ◽  
Phonon Properties

Silicon's material properties, have been studied extensively because of its technological significance in a variety of industries, including microelectronics. Yet, questions surrounding the phonon relaxation times in silicon continue to linger.1,2 Previous theoretical works3-5 have generated qualitative expressions for phonon relaxation times, however these approaches require fitting parameters that cannot be determined reliably. This paper first discusses implementation issues associated with using the Green-Kubo method in molecular dynamics (MD) simulations. We compare various techniques used in similar works and discusses several implementation issues that have arisen in the literature. We then describe an alternative procedure for analyzing the normal modes of a crystal to extract phonon relaxation times. As an example material we study bulk crystalline silicon using equilibrium MD simulations and lattice dynamics. The environment dependent interatomic potential6 is used to model the interactions and frequency dependent phonon properties are extracted from the MD simulations.

scholarly journals Molecular Dynamics Approach in the Comparison of Wild-Type and Mutant Paraoxonase-1 Apoenzyme Form

2015 ◽  
Vol 9 ◽  
pp. BBI.S25626 ◽  
Author(s):  
Khadija Amine ◽  
Lamia Miri ◽  
Adil Naimi ◽  
Rachid Saile ◽  
Abderrahmane El Kharrim ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Active Site ◽  
Paraoxonase 1 ◽  
Wild Type ◽  
Repetitive Movement ◽  
Catalytic Core ◽  
In The Wild ◽  
Dynamics Simulations ◽  
L1 And L2 ◽  
The Impact

There is some evidence linking the mammalian paraoxonase-1 (PON1) loops (L1 and L2) to an increased flexibility and reactivity of its active site with potential substrates. The aim of this work is to study the structural, dynamical, and functional effects of the most flexible regions close to the active site and to determine the impact of mutations on the protein. For both models, wild-type (PON1wild) and PON1 mutant (PON1mut) models, the L1 loop and Q/R and L/M mutations were constructed using MODELLER software. Molecular dynamics simulations of 20 ns at 300 K on fully modeled PON1wild and PON1mut apoenzyme have been done. Detailed analyses of the root-mean-square deviation and fluctuations, H-bonding pattern, and torsion angles have been performed. The PON1wild results were then compared with those obtained for the PON1mut. Our results show that the active site in the wild-type structure is characterized by two distinct movements of opened and closed conformations of the L1 and L2 loops. The alternating and repetitive movement of loops at specific times is consistent with the presence of 11 defined hydrogen bonds. In the PON1mut, these open-closed movements are therefore totally influenced and repressed by the Q/R and L/M mutations. In fact, these mutations seem to impact the PON1mut active site by directly reducing the catalytic core flexibility, while maintaining a significant mobility of the switch regions delineated by the loops surrounding the active site. The impact of the studied mutations on structure and dynamics proprieties of the protein may subsequently contribute to the loss of both flexibility and activity of the PON1 enzyme.

scholarly journals Molecular Simulations suggest Vitamins, Retinoids and Steroids as Ligands binding the Free Fatty Acid Pocket of SARS-CoV-2 Spike Protein

2020 ◽  
Author(s):  
Deborah Shoemark ◽  
Charlotte Colenso ◽  
Christine Toelzer ◽  
Kapil Gupta ◽  
Richard Sessions ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Binding Site ◽  
Spike Protein ◽  
Fatty Acid Binding ◽  
Open Conformation ◽  
Interaction Interface ◽  
Approved Drugs ◽  
Dynamics Simulations ◽  
Fatty Acid Binding Site

<p>Following our recent identification of a fatty acid binding site in the SARS-CoV-2 spike protein (Toelzer <i>et al., Science</i> eabd3255 (2020)), we investigate the binding of linoleate and other potential ligands at this site using molecular dynamics simulations. The results support the hypothesis that linoleate stabilises the locked form of the spike, in which its interaction interface for the ACE2 receptor is occluded. The simulations indicate weaker binding of linoleate to the partially open conformation. Simulations of dexamethasone bound at this site indicate that it binds similarly to linoleate, and thus may also stabilize a locked spike conformation. In contrast, simulations suggest that cholesterol bound at this site may destabilize the locked conformation, and in the open conformation, may preferentially bind at an alternative site in the hinge region between the receptor binding domain and the domain below, which could have functional relevance. We also use molecular docking to identify potential ligands that may bind at the fatty acid binding site, using the Bristol University Docking Engine (BUDE). BUDE docking successfully reproduces the linoleate complex and also supports binding of dexamethasone at the spike fatty acid site. Virtual screening of a library of approved drugs identifies vitamins D, K and A, as well as retinoid ligands with experimentally demonstrated activity against SARS-CoV-2 replication <i>in vitro</i>, as also potentially able to bind at this site. Our data suggest that the fatty acid binding site of the SARS-CoV-2 spike protein may bind a diverse array of candidate ligands. Targeting this site with small molecules, including dietary components such as vitamins, which may stabilise its locked conformation and represents a potential avenue for novel therapeutics or prophylaxis for COVID-19.</p>

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