scholarly journals The model structure of the hammerhead ribozyme formed by RNAs of reciprocal chirality

2020 ◽  
Author(s):  
Eliza Wyszko ◽  
Mariusz Popenda ◽  
Dorota Gudanis ◽  
Joanna Sarzyńska ◽  
Agnieszka Belter ◽  
...  
Keyword(s):  
Hammerhead Ribozyme ◽  
Three Dimensional ◽  
Nuclease Activity ◽  
Base Pairs ◽  
Left Handed ◽  
Low Field ◽  
The Stability ◽  
Dynamics Simulations ◽  
Rna Complexes ◽  
Catalytic Nucleic Acids

RNA-based tools are frequently used to modulate gene expression in living cells. However, the stability and effectiveness of such RNA-based tools is limited by cellular nuclease activity. One way to increase RNA’s resistance to nucleases is to replace its D-ribose backbone with L-ribose isomers. This modification changes chirality of an entire RNA molecule to L-form giving it more chance of survival when introduced into cells. Recently, we have described the activity of left-handed hammerhead ribozyme (L-Rz, L-HH) that can specifically hydrolyze RNA with the opposite chirality at a predetermined location. To understand the structural background of the RNA specific cleavage in a heterochiral complex, we used circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy as well as performed molecular modelling and dynamics simulations of homo- and heterochiral RNA complexes. The active ribozyme-target heterochiral complex showed a mixed chirality as well as low field imino proton NMR signals. We modelled the three dimensional structures of the oligoribonucleotides with their ribozyme counterparts of reciprocal chirality. L- or D-ribozyme formed a stable, homochiral helix 2, and two short double heterochiral helixes 1 and 3 of D- or L-RNA strand thorough irregular Watson-Crick base pairs. The formation of the heterochiral complexes is supported by the result of simulation molecular dynamics. These new observations suggest that L-catalytic nucleic acids can be used as tools in translational biology and diagnostics.

scholarly journals The Stability of a Model Substrate for Topoisomerase 1-Mediated DNA Religation Depends on the Presence of Mismatched Base Pairs

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
William H. Gmeiner ◽  
Freddie Salsbury ◽  
Chris M. Olsen ◽  
Luis A. Marky
Keyword(s):  
Base Pair ◽  
Cleavage Site ◽  
Nucleoside Analogs ◽  
Dna Duplex ◽  
Base Pairs ◽  
Topoisomerase 1 ◽  
Mismatched Base Pair ◽  
The Stability ◽  
Dynamics Simulations ◽  
Dna Complex

Topoisomerase 1 (Top1) enzymes regulate DNA superhelicity by forming covalent cleavage complexes that undergo controlled rotation. Substitution of nucleoside analogs at the +1 position of the DNA duplex relative to the Top1 cleavage site inhibits DNA religation. The reduced efficiency for Top1-mediated religation contributes to the anticancer activity of widely used anticancer drugs including fluoropyrimidines and gemcitabine. In the present study, we report that mismatched base pairs at the +1 position destabilize the duplex DNA components for a model Top1 cleavage complex formation even though one duplex component does not directly include a mismatched base pair. Molecular dynamics simulations reveal G-dU and G-FdU mismatched base pairs, but not a G-T mismatched base pair, increase flexibility at the Top1 cleavage site, and affect coupling between the regions required for the religation reaction to occur. These results demonstrate that substitution of dT analogs into the +1 position of the non-scissile strand alters the stability and flexibility of DNA contributing to the reduced efficiency for Top1-mediated DNA religation. These effects are inherent in the DNA duplex and do not require formation of the Top1:DNA complex. These results provide a biophysical rationale for the inhibition of Top1-mediated DNA religation by nucleotide analog substitution.

scholarly journals Structural Landscape of the Transition from an ssDNA Dumbbell Plus Its Complementary Hairpin to a dsDNA Microcircle Via a Kissing Loop Intermediate

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 3017
Author(s):  
Alberto Mills ◽  
Federico Gago
Keyword(s):  
Model Building ◽  
Three Dimensional ◽  
3D Models ◽  
Base Pairs ◽  
T4 Dna Ligase ◽  
Double Stranded Dna ◽  
Explicit Solvent ◽  
Dynamics Simulations ◽  
Enzyme Recognition ◽  
Kissing Loop

The experimental construction of a double-stranded DNA microcircle of only 42 base pairs entailed a great deal of ingenuity and hard work. However, figuring out the three-dimensional structures of intermediates and the final product can be particularly baffling. Using a combination of model building and unrestrained molecular dynamics simulations in explicit solvent we have characterized the different DNA structures involved along the process. Our 3D models of the single-stranded DNA molecules provide atomic insight into the recognition event that must take place for the DNA bases in the cohesive tail of the hairpin to pair with their complementary bases in the single-stranded loops of the dumbbell. We propose that a kissing loop involving six base pairs makes up the core of the nascent dsDNA microcircle. We also suggest a feasible pathway for the hybridization of the remaining complementary bases and characterize the final covalently closed dsDNA microcircle as possessing two well-defined U-turns. Additional models of the pre-ligation complex of T4 DNA ligase with the DNA dumbbell and the post-ligation pre-release complex involving the same enzyme and the covalently closed DNA microcircle are shown to be compatible with enzyme recognition and gap ligation.

scholarly journals The Shape of Water in Zeolites and Its Impact on Epoxidation Catalysis

2020 ◽  
Author(s):  
Daniel Bregante ◽  
Matthew Chan ◽  
Jun Zhi Tan ◽  
E. Zeynep Ayla ◽  
Christopher P. Nicholas ◽  
...  
Keyword(s):  
Active Sites ◽  
Three Dimensional ◽  
Turnover Rates ◽  
Surface Intermediates ◽  
Discrete Structures ◽  
Correlated Motion ◽  
Solvent Molecules ◽  
Highly Correlated ◽  
The Stability ◽  
Dynamics Simulations

Solvent structures that surround active sites reorganize during catalysis and influence the stability of surface intermediates. Within the pores of a zeolite, H<sub>2</sub>O molecules form hydrogen-bonded structures that differ significantly from bulk H<sub>2</sub>O. Spectroscopic measurements and molecular dynamics simulations show that H<sub>2</sub>O molecules form bulk-like three-dimensional structures within 1.3 nm cages, while H<sub>2</sub>O molecules coalesce into oligomeric one-dimensional chains distributed throughout zeolite frameworks when the pore diameter is smaller than 0.65 nm. The differences between the motifs of these solvent structures provide opportunities to manipulate enthalpy-entropy compensation relationships and significantly increase rates of catalytic turnover events. Here, we explain how the reorganization of these pore size-dependent H<sub>2</sub>O structures during alkene epoxidation catalysis gives rise to entropy gains that increase turnover rates by up to 400-fold. Collectively, this work shows how solvent molecules form discrete structures with highly correlated motion within microporous environments, and that the reorganization of these structures may be controlled to confer stability to reactive intermediates.

scholarly journals The Shape of Water in Zeolites and Its Impact on Epoxidation Catalysis

2020 ◽  
Author(s):  
Daniel Bregante ◽  
Matthew Chan ◽  
Jun Zhi Tan ◽  
E. Zeynep Ayla ◽  
Christopher P. Nicholas ◽  
...  
Keyword(s):  
Active Sites ◽  
Three Dimensional ◽  
Turnover Rates ◽  
Surface Intermediates ◽  
Discrete Structures ◽  
Correlated Motion ◽  
Solvent Molecules ◽  
Highly Correlated ◽  
The Stability ◽  
Dynamics Simulations

Solvent structures that surround active sites reorganize during catalysis and influence the stability of surface intermediates. Within the pores of a zeolite, H<sub>2</sub>O molecules form hydrogen-bonded structures that differ significantly from bulk H<sub>2</sub>O. Spectroscopic measurements and molecular dynamics simulations show that H<sub>2</sub>O molecules form bulk-like three-dimensional structures within 1.3 nm cages, while H<sub>2</sub>O molecules coalesce into oligomeric one-dimensional chains distributed throughout zeolite frameworks when the pore diameter is smaller than 0.65 nm. The differences between the motifs of these solvent structures provide opportunities to manipulate enthalpy-entropy compensation relationships and significantly increase rates of catalytic turnover events. Here, we explain how the reorganization of these pore size-dependent H<sub>2</sub>O structures during alkene epoxidation catalysis gives rise to entropy gains that increase turnover rates by up to 400-fold. Collectively, this work shows how solvent molecules form discrete structures with highly correlated motion within microporous environments, and that the reorganization of these structures may be controlled to confer stability to reactive intermediates.

TMB-iBIOMES: An iBIOMES-Lite Database of Nucleosome Trajectories and Meta-Analysis

2019 ◽  
Author(s):  
Ran Sun ◽  
Zilong Li ◽  
Thomas C. Bishop
Keyword(s):  
Molecular Dynamics ◽  
Meta Analysis ◽  
Parameter Analysis ◽  
Command Line ◽  
Input Output ◽  
Base Pairs ◽  
On Demand ◽  
Left Handed ◽  
Nucleosomal Dna ◽  
Dynamics Simulations

<div>Here we introduce our TMB-iBIOMES database which serves as both a reference for future comparative, on-demand simulations of nucleosomes and a demonstration of iBIOMES-Lite as a tool for managing a laboratory's simulation inventory. TMB-iBIOMES contains over 20 microseconds of all atom molecular dynamics simulations for over 500 different realizations of the nucleosome. For every simulation, the original input, output, de-watered trajectories, RMSD, and DNA helical parameter data are provided. Closely related simulations are grouped together, and a meta-analysis of each group is provided. The data can be navigated in a file browser format or downloaded directly with command line tools. Collectively the simulations provide a novel view of nucleosomal DNA. Compared to DNA free in solution, DNA on the nucleosome is not highly deformed or tightly restricted as determined by DNA helical parameter analysis. The overall conformation is restricted to a specific left-handed super helix, but the range of conformations explored by individual base pairs is larger than that observed for DNA free in solution. </div>

TMB-iBIOMES: An iBIOMES-Lite Database of Nucleosome Trajectories and Meta-Analysis

2019 ◽  
Author(s):  
Ran Sun ◽  
Zilong Li ◽  
Thomas C. Bishop
Keyword(s):  
Molecular Dynamics ◽  
Meta Analysis ◽  
Parameter Analysis ◽  
Command Line ◽  
Input Output ◽  
Base Pairs ◽  
On Demand ◽  
Left Handed ◽  
Nucleosomal Dna ◽  
Dynamics Simulations

<div>Here we introduce our TMB-iBIOMES database which serves as both a reference for future comparative, on-demand simulations of nucleosomes and a demonstration of iBIOMES-Lite as a tool for managing a laboratory's simulation inventory. TMB-iBIOMES contains over 20 microseconds of all atom molecular dynamics simulations for over 500 different realizations of the nucleosome. For every simulation, the original input, output, de-watered trajectories, RMSD, and DNA helical parameter data are provided. Closely related simulations are grouped together, and a meta-analysis of each group is provided. The data can be navigated in a file browser format or downloaded directly with command line tools. Collectively the simulations provide a novel view of nucleosomal DNA. Compared to DNA free in solution, DNA on the nucleosome is not highly deformed or tightly restricted as determined by DNA helical parameter analysis. The overall conformation is restricted to a specific left-handed super helix, but the range of conformations explored by individual base pairs is larger than that observed for DNA free in solution. </div>

scholarly journals Molecular Modeling of Epithiospecifier and Nitrile-Specifier Proteins of Broccoli and Their Interaction with Aglycones

Molecules ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 772 ◽  
Author(s):  
Juan Román ◽  
Dorian González ◽  
Mario Inostroza-Ponta ◽  
Andrea Mahn
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Plant Metabolites ◽  
Secondary Plant Metabolites ◽  
Consensus Amino Acid Sequence ◽  
The Stability ◽  
Dynamics Simulations ◽  
Consensus Amino Acid

Glucosinolates are secondary plant metabolites of Brassicaceae. They exert their effect after enzymatic hydrolysis to yield aglycones, which become nitriles and epithionitriles through the action of epithiospecifier (ESP) and nitrile-specifier proteins (NSP). The mechanism of action of broccoli ESP and NSP is poorly understood mainly because ESP and NSP structures have not been completely characterized and because aglycones are unstable, thus hindering experimental measurements. The aim of this work was to investigate the interaction of broccoli ESP and NSP with the aglycones derived from broccoli glucosinolates using molecular simulations. The three-dimensional structure of broccoli ESP was built based on its amino-acid sequence, and the NSP structure was constructed based on a consensus amino-acid sequence. The models obtained using Iterative Threading ASSEmbly Refinement (I-TASSER) were refined with the OPLS-AA/L all atom force field of GROMACS 5.0.7 and were validated by Veryfy3D and ERRAT. The structures were selected based on molecular dynamics simulations. Interactions between the proteins and aglycones were simulated with Autodock Vina at different pH. It was concluded that pH determines the stability of the complexes and that the aglycone derived from glucoraphanin has the highest affinity to both ESP and NSP. This agrees with the fact that glucoraphanin is the most abundant glucosinolate in broccoli florets.

A Liquid Metal Flow Between Two Coaxial Cylinders System

2019 ◽  
Vol 11 (1) ◽  
pp. 79-86
Author(s):  
Abdelkrim Merah ◽  
Ridha Kelaiaia ◽  
Faiza Mokhtari
Keyword(s):  
Couette Flow ◽  
Metal Flow ◽  
Three Dimensional ◽  
Liquid Sodium ◽  
Taylor Vortex ◽  
Turbulent Regime ◽  
Coaxial Cylinders ◽  
Concentric Cylinders ◽  
Ideal Tool ◽  
The Stability

Abstract The Taylor-Couette flow between two rotating coaxial cylinders remains an ideal tool for understanding the mechanism of the transition from laminar to turbulent regime in rotating flow for the scientific community. We present for different Taylor numbers a set of three-dimensional numerical investigations of the stability and transition from Couette flow to Taylor vortex regime of a viscous incompressible fluid (liquid sodium) between two concentric cylinders with the inner one rotating and the outer one at rest. We seek the onset of the first instability and we compare the obtained results for different velocity rates. We calculate the corresponding Taylor number in order to show its effect on flow patterns and pressure field.

The Role of Hydrophobicity in the Stability and pH-Switchability of (RXDX)4 and Coumarin-RXDX Conjugate β-Sheets

2020 ◽  
Author(s):  
Ryan Weber ◽  
Martin McCullagh
Keyword(s):  
Biological Imaging ◽  
Ph Sensing ◽  
Hydrophobic Residue ◽  
Ideal Candidate ◽  
Self Assembling ◽  
Sensing Applications ◽  
Β Sheets ◽  
The Stability ◽  
Dynamics Simulations

<p>pH-switchable, self-assembling materials are of interest in biological imaging and sensing applications. Here we propose that combining the pH-switchability of RXDX (X=Ala, Val, Leu, Ile, Phe) peptides and the optical properties of coumarin creates an ideal candidate for these materials. This suggestion is tested with a thorough set of all-atom molecular dynamics simulations. We first investigate the dependence of pH-switchabiliy on the identity of the hydrophobic residue, X, in the bare (RXDX)<sub>4</sub> systems. Increasing the hydrophobicity stabilizes the fiber which, in turn, reduces the pH-switchabilty of the system. This behavior is found to be somewhat transferable to systems in which a single hydrophobic residue is replaced with a coumarin containing amino acid. In this case, conjugates with X=Ala are found to be unstable and both pHs while conjugates with X=Val, Leu, Ile and Phe are found to form stable β-sheets at least at neutral pH. The (RFDF)<sub>4</sub>-coumarin conjugate is found to have the largest relative entropy value of 0.884 +/- 0.001 between neutral and acidic coumarin ordering distributions. Thus, we posit that coumarin-(RFDF)<sub>4</sub> containing peptide sequences are ideal candidates for pH-sensing bioelectronic materials.</p>

Handheld Laser Scanner Research

2019 ◽  
Vol 952 (10) ◽  
pp. 47-54
Author(s):  
A.V. Komissarov ◽  
A.V. Remizov ◽  
M.M. Shlyakhova ◽  
K.K. Yambaev
Keyword(s):  
Point Cloud ◽  
Three Dimensional ◽  
Laser Scanner ◽  
Test Site ◽  
Optical Systems ◽  
Advantages And Disadvantages ◽  
Site Survey ◽  
Laser Scanners ◽  
Three Dimensional Models ◽  
The Stability

The authors consider hand-held laser scanners, as a new photogrammetric tool for obtaining three-dimensional models of objects. The principle of their work and the newest optical systems based on various sensors measuring the depth of space are described in detail. The method of simultaneous navigation and mapping (SLAM) used for combining single scans into point cloud is outlined. The formulated tasks and methods for performing studies of the DotProduct (USA) hand-held laser scanner DPI?8X based on a test site survey are presented. The accuracy requirements for determining the coordinates of polygon points are given. The essence of the performed experimental research of the DPI?8X scanner is described, including scanning of a test object at various scanner distances, shooting a test polygon from various scanner positions and building point cloud, repeatedly shooting the same area of the polygon to check the stability of the scanner. The data on the assessment of accuracy and analysis of research results are given. Fields of applying hand-held laser scanners, their advantages and disadvantages are identified.

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