scholarly journals Double-stranded RNA bending by AU-tract sequences

2020 ◽  
Vol 48 (22) ◽  
pp. 12917-12928
Author(s):  
Alberto Marin-Gonzalez ◽  
Clara Aicart-Ramos ◽  
Mikel Marin-Baquero ◽  
Alejandro Martín-González ◽  
Maarit Suomalainen ◽  
...  
Keyword(s):  
Nucleotide Sequence ◽  
Double Helix ◽  
Structural Features ◽  
Sequence Motif ◽  
Microscopy Imaging ◽  
Rna Nanotechnology ◽  
Sequence Dependent ◽  
Structural Deformations ◽  
Dynamics Simulations ◽  
Dna Double Helix

Abstract Sequence-dependent structural deformations of the DNA double helix (dsDNA) have been extensively studied, where adenine tracts (A-tracts) provide a striking example for global bending in the molecule. However, in contrast to dsDNA, sequence-dependent structural features of dsRNA have received little attention. In this work, we demonstrate that the nucleotide sequence can induce a bend in a canonical Watson-Crick base-paired dsRNA helix. Using all-atom molecular dynamics simulations, we identified a sequence motif consisting of alternating adenines and uracils, or AU-tracts, that strongly bend the RNA double-helix. This finding was experimentally validated using atomic force microscopy imaging of dsRNA molecules designed to display macroscopic curvature via repetitions of phased AU-tract motifs. At the atomic level, this novel phenomenon originates from a localized compression of the dsRNA major groove and a large propeller twist at the position of the AU-tract. Moreover, the magnitude of the bending can be modulated by changing the length of the AU-tract. Altogether, our results demonstrate the possibility of modifying the dsRNA curvature by means of its nucleotide sequence, which may be exploited in the emerging field of RNA nanotechnology and might also constitute a natural mechanism for proteins to achieve recognition of specific dsRNA sequences.

scholarly journals Double-stranded RNA bending by AU-tract sequences

2020 ◽  
Author(s):  
Alberto Marin-Gonzalez ◽  
Clara Aicart-Ramos ◽  
Mikel Marin-Baquero ◽  
Alejandro Martín-González ◽  
Maarit Suomalainen ◽  
...  
Keyword(s):  
Double Helix ◽  
Persistence Length ◽  
Arbitrary Sequence ◽  
Sequence Motif ◽  
Double Stranded Rna ◽  
Force Microscopy ◽  
Structural Deformations ◽  
Quaternary Structures ◽  
Dynamics Simulations ◽  
Dna Double Helix

ABSTRACTSequence-dependent structural deformations of the DNA double helix (dsDNA) have been extensively studied, where adenine tracts (A-tracts) provide a striking example for global bending in the molecule. In contrast to dsDNA, much less is known about how the nucleotide sequence affects bending deformations of double-stranded RNA (dsRNA). Using all-atom microsecond long molecular dynamics simulations we found a sequence motif consisting of alternating adenines and uracils, or AU-tracts, that bend the dsRNA helix by locally compressing the major groove. We experimentally tested this prediction using atomic force microscopy (AFM) imaging of long dsRNA molecules containing phased AU-tracts. AFM images revealed a clear intrinsic bend in these AU-tracts molecules, as quantified by a significantly lower persistence length compared to dsRNA molecules of arbitrary sequence. The bent structure of AU-tracts here described might play a role in sequence-specific recognition of dsRNAs by dsRNA-interacting proteins or impact the folding of RNA into intricate tertiary and quaternary structures.

scholarly journals Positively and Negatively Hydrated Counterions in Molecular Dynamics Simulations of DNA Double Helix

2020 ◽  
Vol 65 (6) ◽  
pp. 510
Author(s):  
S. Perepelytsya
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Double Helix ◽  
Dipole Moments ◽  
Hydration Shell ◽  
Minor Groove ◽  
Water Molecules ◽  
Negative Hydration ◽  
Dynamics Simulations ◽  
Dna Double Helix

The DNA double helix is a polyanionic macromolecule that is neutralized in water solutions by metal ions (counterions). The property of counterions to stabilize the water network (positive hydration) or to make it friable (negative hydration) is important in terms of the physical mechanisms of stabilization of the DNA double helix. In the present research, the effects of positive hydration of Na+ counterions and negative hydration of K+ and Cs+ counterions incorporated into the hydration shell of the DNA double helix have been studied using molecular dynamics simulations. The results have shown that the dynamics of the hydration shell of counterions depends on the region of the double helix: minor groove, major groove, and outside the macromolecule. The longest average residence time has been observed for water molecules contacting with the counterions localized in the minor groove of the double helix (about 50 ps for Na+ and lower than 10 ps for K+ and Cs+). The estimated potentials of the mean force for the hydration shells of counterions show that the water molecules are constrained too strongly, and the effect of negative hydration for K+ and Cs+ counterions has not been observed in the simulations. The analysis has shown that the effects of counterion hydration can be described more accurately with water models having lower dipole moments.

scholarly journals Water–DNA interactions as studied by X–ray and neutron fibre diffraction

2004 ◽  
Vol 359 (1448) ◽  
pp. 1237-1248 ◽  
Author(s):  
Watson Fuller ◽  
Trevor Forsyth ◽  
Arumugam Mahendrasingam
Keyword(s):  
Structural Information ◽  
Double Helix ◽  
Water Environment ◽  
Structural Features ◽  
Molecular Conformations ◽  
X Ray ◽  
Biochemical Processes ◽  
Fibre Diffraction ◽  
Dna Double Helix ◽  
High Degree

X–ray fibre–diffraction studies indicate a high degree of stereochemical specificity in interactions between water and the DNA double helix. Evidence for this comes from data that show that the molecular conformations assumed by DNA in fibres are highly reproducible and that the hydration–driven transitions between these conformations are fully reversible. These conformational transitions are induced by varying the relative humidity of the fibre environment and hence its water content. Further evidence for stereochemical specificity comes from the observed dependence of the conformation assumed on the ionic content of the fibre and the nucleotide sequence of the DNA. For some transitions, information on stereochemical pathways has come from real–time X–ray fibre diffraction using synchrotron radiation; information on the location of water with respect to the double helix for a number of DNA conformations has come from neutron fibre diffraction. This structural information from fibre–diffraction studies of DNA is complemented by information from X–ray single–crystal studies of oligonucleotides. If the biochemical processes involving DNA have evolved to exploit the structural features observed in DNA fibres and oligonucleotide single crystals, the challenges in developing alternatives to a water environment can be expected to be very severe.

Polyamine derivatives as potential bisintercalators with antiproliferative activity

2016 ◽  
Vol 4 ◽  
pp. 9-15
Author(s):  
Marta Szumilak
Keyword(s):  
Ethidium Bromide ◽  
Antiproliferative Activity ◽  
Double Helix ◽  
Structural Features ◽  
Discovery Studio ◽  
Polycyclic Aromatic ◽  
Ic50 Values ◽  
Dna Double Helix ◽  
Polyamine Derivatives

Bisntercalators are very interesting group of compounds with potential antitumor activity. They interact reversibly with DNA double helix. These agents share common structural features such as the presence of two, planar, polycyclic aromatic or heteroaromatic systems separated by a spacer chain which must be long enough to enable double intercalation between base pairs. The unique chemical structure of these compounds provides numerous modifications within their structure resulting either in higher activity or increased selectivity toward tumor cells. Within the framework of the project, new polyamine derivatives containing dimeric phthalimide, quinoline, cinnoline and chromone moieties were obtained. Three different polyamines: 1,4-bis(3-aminopropyl)piperazine, 4,9-dioxa-1,12-dodecanediamine, 3,3’-diamino-N-methyldipropylamine were used as linkers. The biological activity of compounds was assessed in vitro in a highly aggressive melanoma cell line A375. Quinoline derivatives were found to have a higher antiproliferative activity than cinnoline ones. The lowest IC50 values, below 20 μM, were obtained for quinoline and 2H-chromene-2,4(3H)-dione derivatives. Quinoline diamides were more efficient than cinnoline ones. Polyamine diimides containing phthalimide moieties demonstrated no inhibitory activities against melanoma cells. Preliminary studies of mechanism of action have shown that obtained derivatives were capable of quenching the fluorescence of ethidium bromide-DNA complex, indicating that they bound to ds-DNA in competition with ethidium bromide for binding sites. All the compounds were also subjected to preliminary in silico ADME screening by evaluating their theoretical drug-likeness and physicochemical properties using Discovery Studio 3.0 obtained from Accelrys. Compounds meeting the required ADME and drug-likeness criteria were selected.

scholarly journals C3′ Stereocentre of Furanose Determines the Helicity of Double-Stranded Nucleic Acids: Towards Etiology of Nucleic Acids

2020 ◽  
Author(s):  
Anuj Kumar ◽  
Amol Tagad ◽  
G. Naresh Patwari
Keyword(s):  
Molecular Dynamics ◽  
Nucleic Acids ◽  
Structural Transition ◽  
Double Helix ◽  
Helical Structure ◽  
Structural Features ◽  
Toggle Switch ◽  
Helix Structure ◽  
Double Helix Structure ◽  
Dynamics Simulations

ABSTRACTRibose containing double-stranded nucleic acids exhibit helical structure, whereas sugar modified (xeno) nucleic acids may exhibit different structural features. The structural landscape of four stereo variants of furanosal nucleic acids and their C2′ deoxy counterparts, explored with molecular dynamics simulations, suggest that the configuration at the C3′ position plays a pivotal role in determining the helicity. The C3′ stereocentre acts as toggle-switch for the helix to ladder structural transformation by changing the nature of intra-strand interactions resulting in the optimal helices for ribose containing double-stranded nucleic acids. Interestingly, lack of chirality at the C2′ position results in better quality helices than inversion of stereochemistry relative to ribose. The etiology of furanosal-RNA over other furanoses can be hypothesized based on the helical structure, which can effectively be exploited by the biological machinery.SIGNIFICANCEThe double helix structure of furanosal RNA is governed by the configuration at the C3′ position. Furanose sugars such as xylose and lyxose where in the configuration at the C3′ position is inverted relative to the ribose do not form double helix structure, instead result in ladder-like structure. The configuration at the C3′ position acts as a toggle switch for the helix to ladder structural transition. Among four furanose sugars viz., ribose, arabinose, xylose, and lyxose, the double-stranded nucleic acids incorporating ribose form helices with best aspect ratio between major and minor grooves.

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.

scholarly journals MUTABLE R-NAVAJO ALLELES OF CYCLIC ORIGIN IN MAIZE

Genetics ◽  
1973 ◽  
Vol 73 (2) ◽  
pp. 273-296
Author(s):  
R Alexander Brink ◽  
Elizabeth Williams
Keyword(s):  
Nucleotide Sequence ◽  
Gene Action ◽  
Double Helix ◽  
Donor Site ◽  
Chromosome Breakage ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Unstable Compound ◽  
The Stability ◽  
Dna Double Helix

ABSTRACT The generation in cyclic fashion of 26 mutable R-Navajo (mRnj) alleles in maize involved transposition of a non-specific repressor of gene action, Modulator (Mp), first away from, and then back to, the R locus represented by the R-Navajo (Rnj) all ele on chromosome 10. The mPnj alleles reconstituted in this way vaned widely, and continuously, in mutability to Rnj-that is, in transposition of Mp away from the R locus, thus derepressing the Rnj gene. They were alike, or nearly so, however, in activating Ds chromosome breakage and in increasing the stability of variegated pericarp, another unstable compound allele comprising Mp conjoined with Prr on chromosomal 1. These latter two phenomena are based primarily on loci elsewhere in the genome. It is postulated that the 26 reconstituted mRnj alleles carry a common Mp which, however, is intercalated at a different site within each allele. Nucleotide sequence in the regions adjacent to Mp is assumed to determine the frequency with which a form of micro-nondisjunction occurs whereby Mp is released from a donor site. Transposition to a new site is interpreted in terms of a chromosome model that gives effect to nicking, or single strand breaks, occurring throughout the genome as a prerequisite to unwinding, strand separation, and replication, of the DNA double helix.

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