Browse
Submit Data
Databases
API
Help

Dataset Information

16 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Guiding the folding of G-quadruplexes through loop residue interactions.

ABSTRACT: A G-rich sequence was designed to allow folding into either a stable parallel or hybrid-type topology. With the parent sequence featuring coexisting species, various related sequences with single and double mutations and with a shortened central propeller loop affected the topological equilibrium. Two simple modifications, likewise introduced separately to all sequences, were employed to lock folds into one of the topologies without noticeable structural alterations. The unique combination of sequence mutations, high-resolution NMR structural information, and the thermodynamic stability for both topological competitors identified critical loop residue interactions. In contrast to first loop residues, which are mostly disordered and exposed to solvent in both propeller and lateral loops bridging a narrow groove, the last loop residue in a lateral three-nucleotide loop is engaged in stabilizing stacking interactions. The propensity of single-nucleotide loops to favor all-parallel topologies by enforcing a propeller-like conformation of an additional longer loop is shown to result from their preference in linking two outer tetrads of the same tetrad polarity. Taken together, the present studies contribute to a better structural and thermodynamic understanding of delicate loop interactions in genomic and artificially designed quadruplexes, e.g. when employed as therapeutics or in other biotechnological applications.

SUBMITTER: Jana J

PROVIDER: S-EPMC9262619 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Rational design of guiding elements to control folding topology in i-motifs with multiple quadruplexes.

Project description:Nucleic acids are versatile scaffolds that accommodate a wide range of precisely defined operational characteristics. Rational design of sensing, molecular computing, nanotechnology, and other nucleic acid devices requires precise control over folding conformations in these macromolecules. Here, we report a new approach that empowers well-defined conformational transitions in DNA molecular devices. Specifically, we develop tools for precise folding of multiple DNA quadruplexes (i-motifs) within the same oligonucleotide strand. To accomplish this task, we modify a DNA strand with kinetic control elements (hairpins and double stranded stems) that fold on a much faster timescale and consequently guide quadruplexes toward the targeted folding topology. To demonstrate that such guiding elements indeed facilitate formation of the targeted folding topology, we thoroughly characterize the folding/unfolding transitions through a combination of thermodynamic techniques, size exclusion chromatography (SEC) and small-angle X-ray scattering (SAXS). Furthermore, we extend SAXS capabilities to produce a direct insight on the shape and dimensions of the folded quadruplexes by computing their electron density maps from solution scattering data.

| S-EPMC8210535 | biostudies-literature

R-loop associated G-quadruplexes reinforce CTCF interactions

Project description:We report that three-stranded R-loop structures facilitate CTCF binding genome-wide through the formation of G-quadruplex (G4) structures. Genome-wide assays of CTCF and R-loop formation under various treatment conditions reveal that R-loop removal and G4 stabilization can both alter CTCF occupancy, and these changes are associated with alterations in gene expression and chromatin organization.

2023-06-26 | GSE208145 | GEO

Characterization of G-Quadruplexes Folding/Unfolding Dynamics and Interactions with Proteins from Single-Molecule Force Spectroscopy.

Project description:G-quadruplexes (G4s) are stable secondary nucleic acid structures that play crucial roles in many fundamental biological processes. The folding/unfolding dynamics of G4 structures are associated with the replication and transcription regulation functions of G4s. However, many DNA G4 sequences can adopt a variety of topologies and have complex folding/unfolding dynamics. Determining the dynamics of G4s and their regulation by proteins remains challenging due to the coexistence of multiple structures in a heterogeneous sample. Here, in this mini-review, we introduce the application of single-molecule force-spectroscopy methods, such as magnetic tweezers, optical tweezers, and atomic force microscopy, to characterize the polymorphism and folding/unfolding dynamics of G4s. We also briefly introduce recent studies using single-molecule force spectroscopy to study the molecular mechanisms of G4-interacting proteins.

| S-EPMC8615981 | biostudies-literature

R-loop associated G-quadruplexes reinforce CTCF interactions

Project description:R-loop associated G-quadruplexes reinforce CTCF interactions

| PRJNA858467 | ENA

Modulation of RNA polymerase activity through the trigger loop folding.

Project description:Folding of the trigger loop of RNA polymerase promotes nucleotide addition through creating a closed, catalytically competent conformation of the active center. Here, we discuss the impact of adjacent RNA polymerase elements, including the F loop and the jaw domain, as well as external regulatory factors on the trigger loop folding and catalysis.

| S-EPMC3023635 | biostudies-literature

CONFOLD: Residue-residue contact-guided ab initio protein folding.

Project description:Predicted protein residue-residue contacts can be used to build three-dimensional models and consequently to predict protein folds from scratch. A considerable amount of effort is currently being spent to improve contact prediction accuracy, whereas few methods are available to construct protein tertiary structures from predicted contacts. Here, we present an ab initio protein folding method to build three-dimensional models using predicted contacts and secondary structures. Our method first translates contacts and secondary structures into distance, dihedral angle, and hydrogen bond restraints according to a set of new conversion rules, and then provides these restraints as input for a distance geometry algorithm to build tertiary structure models. The initially reconstructed models are used to regenerate a set of physically realistic contact restraints and detect secondary structure patterns, which are then used to reconstruct final structural models. This unique two-stage modeling approach of integrating contacts and secondary structures improves the quality and accuracy of structural models and in particular generates better β-sheets than other algorithms. We validate our method on two standard benchmark datasets using true contacts and secondary structures. Our method improves TM-score of reconstructed protein models by 45% and 42% over the existing method on the two datasets, respectively. On the dataset for benchmarking reconstructions methods with predicted contacts and secondary structures, the average TM-score of best models reconstructed by our method is 0.59, 5.5% higher than the existing method. The CONFOLD web server is available at http://protein.rnet.missouri.edu/confold/.

| S-EPMC4509844 | biostudies-literature

Frustrated folding of guanine quadruplexes in telomeric DNA.

Project description:Human chromosomes terminate in long, single-stranded, DNA overhangs of the repetitive sequence (TTAGGG)n. Sets of four adjacent TTAGGG repeats can fold into guanine quadruplexes (GQ), four-stranded structures that are implicated in telomere maintenance and cell immortalization and are targets in cancer therapy. Isolated GQs have been studied in detail, however much less is known about folding in long repeat sequences. Such chains adopt an enormous number of configurations containing various arrangements of GQs and unfolded gaps, leading to a highly frustrated energy landscape. To better understand this phenomenon, we used mutagenesis, thermal melting, and global analysis to determine stability, kinetic, and cooperativity parameters for GQ folding within chains containing 8-12 TTAGGG repeats. We then used these parameters to simulate the folding of 32-repeat chains, more representative of intact telomeres. We found that a combination of folding frustration and negative cooperativity between adjacent GQs increases TTAGGG unfolding by up to 40-fold, providing an abundance of unfolded gaps that are potential binding sites for telomeric proteins. This effect was most pronounced at the chain termini, which could promote telomere extension by telomerase. We conclude that folding frustration is an important and largely overlooked factor controlling the structure of telomeric DNA.

| S-EPMC8034632 | biostudies-literature

Identification of the minimal protein-folding nucleus through loop-entropy perturbations.

Project description:To explore the plasticity and structural constraints of the protein-folding nucleus we have constructed through circular permutation four topological variants of the ribosomal protein S6. In effect, these topological variants represent entropy mutants with maintained spatial contacts. The proteins were characterized at two complementary levels of detail: by phi-value analysis estimating the extent of contact formation in the transition-state ensemble and by Hammond analysis measuring the site-specific growth of the folding nucleus. The results show that, although the loop-entropy alterations markedly influence the appearance and structural location of the folding nucleus, it retains a common motif of one helix docking against two strands. This nucleation motif is built around a shared subset of side chains in the center of the hydrophobic core but extends in different directions of the S6 structure following the permutant-specific differences in local loop entropies. The adjustment of the critical folding nucleus to alterations in loop entropies is reflected by a direct correlation between the phi-value change and the accompanying change in local sequence separation.

| S-EPMC1449650 | biostudies-literature

Inhibited complete folding of consecutive human telomeric G-quadruplexes.

Project description:Noncanonical DNA structures, termed G-quadruplexes, are present in human genomic DNA and are important elements in many DNA metabolic processes. Multiple sites in the human genome have G-rich DNA stretches able to support formation of several consecutive G-quadruplexes. One of those sites is the telomeric overhang region that has multiple repeats of TTAGGG and is tightly associated with both cancer and aging. We investigated the folding of consecutive G-quadruplexes in both potassium- and sodium-containing solutions using single-molecule FRET spectroscopy, circular dichroism, thermal melting and molecular dynamics simulations. Our observations show coexistence of partially and fully folded DNA, the latter consisting of consecutive G-quadruplexes. Following the folding process over hours in sodium-containing buffers revealed fast G-quadruplex folding but slow establishment of thermodynamic equilibrium. We find that full consecutive G-quadruplex formation is inhibited by the many DNA structures randomly nucleating on the DNA, some of which are off-path conformations that need to unfold to allow full folding. Our study allows describing consecutive G-quadruplex formation in both nonequilibrium and equilibrium conditions by a unified picture, where, due to the many possible DNA conformations, full folding with consecutive G-quadruplexes as beads on a string is not necessarily achieved.

| S-EPMC9976873 | biostudies-literature

Stability of intramolecular quadruplexes: sequence effects in the central loop.

Project description:Hundreds of thousands of putative quadruplex sequences have been found in the human genome. It is important to understand the rules that govern the stability of these intramolecular structures. In this report, we analysed sequence effects in a 3-base-long central loop, keeping the rest of the quadruplex unchanged. A first series of 36 different sequences were compared; they correspond to the general formula GGGTTTGGGHNHGGGTTTGGG. One clear rule emerged from the comparison of all sequence motifs: the presence of an adenine at the first position of the loop was significantly detrimental to stability. In contrast, adenines have no detrimental effect when present at the second or third position of the loop. Cytosines may either have a stabilizing or destabilizing effect depending on their position. In general, the correlation between the T(m) or DeltaG degrees in sodium and potassium was weak. To determine if these sequence effects could be generalized to different quadruplexes, specific loops were tested in different sequence contexts. Analysis of 26 extra sequences confirmed the general destabilizing effect of adenine as the first base of the loop(s). Finally, analysis of some of the sequences by microcalorimetry (DSC) confirmed the differences found between the sequence motifs.

| S-EPMC2760802 | biostudies-other

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data