scholarly journals The emergence of sequence-dependent structural motifs in stretched, torsionally constrained DNA

2019 ◽  
Author(s):  
Jack W Shepherd ◽  
R J Greenall ◽  
M I J Probert ◽  
Agnes Noy ◽  
Mark C. Leake
Keyword(s):  
Structural Changes ◽  
Periodic Structures ◽  
Helical Structure ◽  
Specific Response ◽  
Base Pairs ◽  
Structural Motifs ◽  
Double Helical Structure ◽  
Physiological Relevance ◽  
Stable Periodic ◽  
Dynamics Simulations

ABSTRACTThe double-helical structure of DNA results from canonical base pairing and stacking interactions. However, variations from steady-state conformations result from mechanical perturbations in cells. These different topologies have physiological relevance but their dependence on sequence remains unclear. Here, we use molecular dynamics simulations to show that sequence differences result in markedly different structural motifs upon physiological twisting and stretching. We simulated overextension on four different sequences of DNA ((AA)12, (AT)12, (GG)12and (GC)12) with supercoiling densities within the physiological range. We found that DNA denatures in the majority of stretching simulations, surprisingly including those with overtwisted DNA. GC-rich sequences were observed to be more stable than AT-rich, with the specific response dependent on base pair ordering. Furthermore, we found that (AT)12forms stable periodic structures with non-canonical hydrogen bonds in some regions and non-canonical stacking in others, whereas (GC)12forms a stacking motif of four base pairs independent of supercoiling density. Our results demonstrate that 20-30% DNA extension is sufficient for breaking B-DNA around and significantly above cellular supercoiling, and that the DNA sequence is crucial for understanding structural changes under mechanical stress. Our findings have important implications for the activities of protein machinery interacting with DNA in all cells.

scholarly journals The emergence of sequence-dependent structural motifs in stretched, torsionally constrained DNA

2020 ◽  
Vol 48 (4) ◽  
pp. 1748-1763 ◽  
Author(s):  
Jack W Shepherd ◽  
Robert J Greenall ◽  
Matt I J Probert ◽  
Agnes Noy ◽  
Mark C Leake
Keyword(s):  
Structural Changes ◽  
Periodic Structures ◽  
Helical Structure ◽  
Specific Response ◽  
Base Pairs ◽  
Structural Motifs ◽  
Double Helical Structure ◽  
Physiological Relevance ◽  
Stable Periodic ◽  
Dynamics Simulations

Abstract The double-helical structure of DNA results from canonical base pairing and stacking interactions. However, variations from steady-state conformations resulting from mechanical perturbations in cells have physiological relevance but their dependence on sequence remains unclear. Here, we use molecular dynamics simulations showing sequence differences result in markedly different structural motifs upon physiological twisting and stretching. We simulate overextension on different sequences of DNA ((AA)12, (AT)12, (CC)12 and (CG)12) with supercoiling densities at 200 and 50 mM salt concentrations. We find that DNA denatures in the majority of stretching simulations, surprisingly including those with over-twisted DNA. GC-rich sequences are observed to be more stable than AT-rich ones, with the specific response dependent on the base pair order. Furthermore, we find that (AT)12 forms stable periodic structures with non-canonical hydrogen bonds in some regions and non-canonical stacking in others, whereas (CG)12 forms a stacking motif of four base pairs independent of supercoiling density. Our results demonstrate that 20–30% DNA extension is sufficient for breaking B-DNA around and significantly above cellular supercoiling, and that the DNA sequence is crucial for understanding structural changes under mechanical stress. Our findings have important implications for the activities of protein machinery interacting with DNA in all cells.

scholarly journals Destabilization of DNA duplexes by oxidative damage at guanine: implications for lesion recognition and repair

2008 ◽  
Vol 5 (suppl_3) ◽  
pp. 191-198 ◽  
Author(s):  
Supat Jiranusornkul ◽  
Charles A Laughton
Keyword(s):  
Oxidative Damage ◽  
Structural Changes ◽  
Double Helix ◽  
Dependent Manner ◽  
Dna Duplexes ◽  
Lesion Site ◽  
Base Pairs ◽  
Energetic Analysis ◽  
Dynamics Simulations ◽  
Dna Double Helix

We have used molecular dynamics simulations to study the structure and dynamics of a range of DNA duplexes containing the 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapydG) lesion that can result from oxidative damage at guanine. Compared to the corresponding undamaged DNA duplexes, FapydG-containing duplexes show little gross structural changes—the damaged base remains stacked in to the DNA double helix and retains hydrogen bonds to its cytosine partner. However, the experimentally observed reduction in DNA stability that accompanies lesion formation can be explained by a careful energetic analysis of the simulation data. Irrespective of the nature of the base pairs on either side of the lesion site, conversion of a guanine to a FapydG base results in increased dynamical flexibility in the base (but not in the DNA as a whole) that significantly weakens its hydrogen-bonding interactions. Surprisingly, the stacking interactions with its neighbours are not greatly altered. The formamido group adopts a non-planar conformation that can interact significantly and in a sequence-dependent manner with its 3′-neighbour. We conclude that the recognition of FapydG lesions by the repair protein formamidopyrimidine-DNA glycosylase probably does not involve the protein capturing an already-extrahelical FapydG base, but rather it relies on detecting alterations to the DNA structure and flexibility created by the lesion site.

Computational determination of radiation damage effects on DNA structure

Open Physics ◽  
2003 ◽  
Vol 1 (1) ◽  
Author(s):  
Miroslav Pinak
Keyword(s):  
Structural Changes ◽  
Double Helix ◽  
Helical Structure ◽  
Electrostatic Energy ◽  
Necessary Condition ◽  
Enzyme Complex ◽  
Repair Enzyme ◽  
Thymine Dimer ◽  
Thymine Glycol ◽  
Double Helical Structure

AbstractMolecular dynamics (MD) studies of several radiation originated lesions on the DNA molecules are presented. The pyrimidine lesions (cytosinyl radical, thymine dimer, thymine glycol) and purine lesion (8-oxoguanine) were subjected to the MD simulations for several hundred picoseconds using MD simulation code AMBER 5.0 (4.0). The simulations were performed for fully dissolved solute molecules in water. Significant structural changes in the DNA double helical structure were observed in all cases which may be categorized as: a) the breaking of hydrogen bonds network between complementary bases and resulted opening of the double helix (cytosinyl, radical, 8-oxoguanine); b) the sharp bending of the DNA helix centered at the lesion site (thymine dimer, thymine glycol); and c) the flippingout of adenine on the strand complementary to the lesion (8-oxoguanine). These changes related to the overall collapsing of the double helical structure around the lesion, are expected to facilitate the docking of the repair enzyme into the DNA in the formation of DNA-enzyme complex. The stable DNA-enzyme complex is a necessary condition for the onset of the enzymatic repair process. In addition to structural changes, specific values of electrostatic interaction energy were determined at several lesion sites (thymine dimer, thymine glycol and 8-oxoguanine). This lesion-specific electrostatic energy is a factor that enables repair enzyme to discriminate lesion from the native site during the scanning of the DNA surface.

An infrared study of the influence of growth media and myo-inositol on structural changes in DNA induced by dehydration and ultraviolet light

1968 ◽  
Vol 14 (8) ◽  
pp. 841-852 ◽  
Author(s):  
S. J. Webb ◽  
M. D. Dumasia
Keyword(s):  
Structural Changes ◽  
Bound Water ◽  
Helical Structure ◽  
Growth Media ◽  
Minimal Salt Medium ◽  
Infrared Study ◽  
Bacterial Dna ◽  
Double Helical Structure ◽  
Spectral Shifts ◽  
Absorption Frequencies

The infrared spectra of films of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and synthetic polynucleotides have been studied under varying degrees of relative humidity (R.H.) in the presence and absence of myo-inositol. In addition the effect of 2537 Å light (ultraviolet) on the hydration of DNA has been investigated. As other researchers have shown, when the R.H. is lowered shifts in the P=O and C=O absorption frequencies occur. These shifts seem to be associated with the removal of approximately 12 molecules of water/nucleotide and all are prevented by the presence of 2 molecules of inositol/nucleotide during desiccation. The irradiation of DNA at 75% R.H. with ultraviolet also produces spectral shifts which appear to arise as a result of bound water molecules moving from P=O and C=O groups.The response of bacterial DNA to desiccation appears to depend on the medium in which the cells are grown. The DNA from cells grown in a minimal salts medium is less hydrated at a given R.H. level than the DNA from cells grown in an enriched medium. This loss of water-adsorbing sites is considered to be due to a physiological replacement of water on the DNA of cells grown on minimal salt medium by amino acids or proteins. RNA and polynucleotides are less hydrated than DNA, which is assumed to be due to their lack of an ordered double helical structure. Of the synthetic polynucleotides poly-I was found to most closely resemble the behavior of DNA. The ability of inositol to prevent spectral shifts in DNA caused by desiccation and irradiation tends to substantiate the suggestion that it preserves the biological integrity of cells and viruses during stress by combining with DNA.

Tuning the Electric Field Response of MOFs by Rotatable Dipolar Linkers

2019 ◽  
Author(s):  
Johannes P. Dürholt ◽  
Babak Farhadi Jahromi ◽  
Rochus Schmid
Keyword(s):  
Electric Field ◽  
Electric Fields ◽  
Structural Changes ◽  
Dielectric Behavior ◽  
Two Dimensions ◽  
Dielectric Constants ◽  
Electric Response ◽  
Dipole Strength ◽  
Metal Organic ◽  
Dynamics Simulations

Recently the possibility of using electric fields as a further stimulus to trigger structural changes in metal-organic frameworks (MOFs) has been investigated. In general, rotatable groups or other types of mechanical motion can be driven by electric fields. In this study we demonstrate how the electric response of MOFs can be tuned by adding rotatable dipolar linkers, generating a material that exhibits paralectric behavior in two dimensions and dielectric behavior in one dimension. The suitability of four different methods to compute the relative permittivity κ by means of molecular dynamics simulations was validated. The dependency of the permittivity on temperature T and dipole strength μ was determined. It was found that the herein investigated systems exhibit a high degree of tunability and substantially larger dielectric constants as expected for MOFs in general. The temperature dependency of κ obeys the Curie-Weiss law. In addition, the influence of dipolar linkers on the electric field induced breathing behavior was investigated. With increasing dipole moment, lower field strength are required to trigger the contraction. These investigations set the stage for an application of such systems as dielectric sensors, order-disorder ferroelectrics or any scenario where movable dipolar fragments respond to external electric fields.

scholarly journals Protein Sensing Device with Multi-Recognition Ability Composed of Self-Organized Glycopeptide Bundle

2020 ◽  
Vol 22 (1) ◽  
pp. 366
Author(s):  
Mao Arai ◽  
Tomohiro Miura ◽  
Yuriko Ito ◽  
Takatoshi Kinoshita ◽  
Masahiro Higuchi
Keyword(s):  
Binding Site ◽  
Lipid Bilayer ◽  
Structural Changes ◽  
Bilayer Membrane ◽  
Lipid Bilayer Membrane ◽  
Target Protein ◽  
Self Organization ◽  
Specific Response ◽  
Target Proteins ◽  
Recognition Ability

We designed and synthesized amphiphilic glycopeptides with glucose or galactose at the C-terminals. We observed the protein-induced structural changes of the amphiphilic glycopeptide assembly in the lipid bilayer membrane using transmission electron microscopy (TEM) and Fourier transform infrared reflection-absorption spectra (FTIR-RAS) measurements. The glycopeptides re-arranged to form a bundle that acted as an ion channel due to the interaction among the target protein and the terminal sugar groups of the glycopeptides. The bundle in the lipid bilayer membrane was fixed on a gold-deposited quartz crystal microbalance (QCM) electrode by the membrane fusion method. The protein-induced re-arrangement of the terminal sugar groups formed a binding site that acted as a receptor, and the re-binding of the target protein to the binding site induced the closing of the channel. We monitored the detection of target proteins by the changes of the electrochemical properties of the membrane. The response current of the membrane induced by the target protein recognition was expressed by an equivalent circuit consisting of resistors and capacitors when a triangular voltage was applied. We used peanut lectin (PNA) and concanavalin A (ConA) as target proteins. The sensing membrane induced by PNA shows the specific response to PNA, and the ConA-induced membrane responded selectively to ConA. Furthermore, PNA-induced sensing membranes showed relatively low recognition ability for lectin from Ricinus Agglutinin (RCA120) and mushroom lectin (ABA), which have galactose binding sites. The protein-induced self-organization formed the spatial arrangement of the sugar chains specific to the binding site of the target protein. These findings demonstrate the possibility of fabricating a sensing device with multi-recognition ability that can recognize proteins even if the structure is unknown, by the protein-induced self-organization process.

Hyaluronic acid: a double-helical structure in the presence of potassium at low pH and found also with the cations ammonium, rubidium and caesium

1977 ◽  
Vol 117 (1) ◽  
pp. 113-135 ◽  
Author(s):  
J.K. Sheehan ◽  
K.H. Gardner ◽  
E.D.T. Atkins
Keyword(s):  
Hyaluronic Acid ◽  
Helical Structure ◽  
Low Ph ◽  
Double Helical Structure

scholarly journals Cofilin is a pH sensor for actin free barbed end formation: role of phosphoinositide binding

2008 ◽  
Vol 183 (5) ◽  
pp. 865-879 ◽  
Author(s):  
Christian Frantz ◽  
Gabriela Barreiro ◽  
Laura Dominguez ◽  
Xiaoming Chen ◽  
Robert Eddy ◽  
...  
Keyword(s):  
Actin Filament ◽  
Structural Changes ◽  
Ph Sensor ◽  
Ph Sensitive ◽  
Actin Binding ◽  
Filamentous Actin ◽  
Filament Dynamics ◽  
Ph Dependent ◽  
Dynamics Simulations

Newly generated actin free barbed ends at the front of motile cells provide sites for actin filament assembly driving membrane protrusion. Growth factors induce a rapid biphasic increase in actin free barbed ends, and we found both phases absent in fibroblasts lacking H+ efflux by the Na-H exchanger NHE1. The first phase is restored by expression of mutant cofilin-H133A but not unphosphorylated cofilin-S3A. Constant pH molecular dynamics simulations and nuclear magnetic resonance (NMR) reveal pH-sensitive structural changes in the cofilin C-terminal filamentous actin binding site dependent on His133. However, cofilin-H133A retains pH-sensitive changes in NMR spectra and severing activity in vitro, which suggests that it has a more complex behavior in cells. Cofilin activity is inhibited by phosphoinositide binding, and we found that phosphoinositide binding is pH-dependent for wild-type cofilin, with decreased binding at a higher pH. In contrast, phosphoinositide binding by cofilin-H133A is attenuated and pH insensitive. These data suggest a molecular mechanism whereby cofilin acts as a pH sensor to mediate a pH-dependent actin filament dynamics.

scholarly journals On the dynamics of some small structural motifs in rRNA upon ligand binding

2008 ◽  
Vol 73 (1) ◽  
pp. 41-53
Author(s):  
Aleksandra Rakic ◽  
Petar Mitrasinovic
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Binding Sites ◽  
De Novo ◽  
Reference Structure ◽  
Base Pairs ◽  
Rna Sequences ◽  
Conformational Model ◽  
Thermodynamic Variables ◽  
Dynamics Simulations

The present study characterizes using molecular dynamics simulations the behavior of the GAA (1186-1188) hairpin triloops with their closing c-g base pairs in large ribonucleoligand complexes (PDB IDs: 1njn, 1nwy, 1jzx). The relative energies of the motifs in the complexes with respect to that in the reference structure (unbound form of rRNA; PDB ID: 1njp) display the trends that agree with those of the conformational parameters reported in a previous study1 utilizing the de novo pseudotorsional (?,?) approach. The RNA regions around the actual RNA-ligand contacts, which experience the most substantial conformational changes upon formation of the complexes were identified. The thermodynamic parameters, based on a two-state conformational model of RNA sequences containing 15, 21 and 27 nucleotides in the immediate vicinity of the particular binding sites, were evaluated. From a more structural standpoint, the strain of a triloop, being far from the specific contacts and interacting primarily with other parts of the ribosome, was established as a structural feature which conforms to the trend of the average values of the thermodynamic variables corresponding to the three motifs defined by the 15-, 21- and 27-nucleotide sequences. From a more functional standpoint, RNA-ligand recognition is suggested to be presumably dictated by the types of ligands in the complexes.

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