Folding Potential Research Articles

RNA G-quadruplex structures exist and function in vivo in plants

BackgroundGuanine-rich sequences are able to form complex RNA structures termed RNA G-quadruplexes in vitro. Because of their high stability, RNA G-quadruplexes are proposed to exist in vivo and are suggested to be associated with important biological relevance. However, there is a lack of direct evidence for RNA G-quadruplex formation in living eukaryotic cells. Therefore, it is unclear whether any purported functions are associated with the specific sequence content or the formation of an RNA G-quadruplex structure.ResultsUsing rG4-seq, we profile the landscape of those guanine-rich regions with the in vitro folding potential in the Arabidopsis transcriptome. We find a global enrichment of RNA G-quadruplexes with two G-quartets whereby the folding potential is strongly influenced by RNA secondary structures. Using in vitro and in vivo RNA chemical structure profiling, we determine that hundreds of RNA G-quadruplex structures are strongly folded in both Arabidopsis and rice, providing direct evidence of RNA G-quadruplex formation in living eukaryotic cells. Subsequent genetic and biochemical analyses show that RNA G-quadruplex folding is able to regulate translation and modulate plant growth.ConclusionsOur study reveals the existence of RNA G-quadruplex in vivo and indicates that RNA G-quadruplex structures act as important regulators of plant development and growth.

π-Stacking Driven Aggregation and Folding of Squaramides.

Competing noncovalent interactions play a pivotal role in the folding and assembly of three-dimensional structures, especially in flexible molecules. Calculations using density functional theory reveal that two squaramide rings aggregate to form a slipped antiparallel π-stacked dimer with high propensity. This π-π stacking interaction is used to design foldamers in which the squaramides are tethered by a simple methylene bridge, and consequently, the structure folds on to itself incorporating a "turn" element. The variation in relative energy with respect to change in dihedral angle for these foldamers show that for all the structures two rings are displaced in space and the folding potential is asymmetric, starting from seemingly symmetric molecules. The addition of successive squaramide rings connected with simple methylene bridges leads to the formation of higher-order structures with a "Turn-Stack-Turn" structural motif. The "Turn-Stack-Turn" motif can be used in designing new synthetic foldamers which could potentially mimic closely related biological systems. Further, it was found that the aggregation of the folded structures was energetically favored over the unfolded structures. The present set of calculations are important in light of the fact that these simple methylene bridged squaramide rings present synthetic challenges.

Pion-nucleus elastic scattering studies within the microscopic folding potential

The pion-nucleus elastic scattering cross sections are calculated and compared to the data of pion scattering on 28Si, 58Ni, 208Pb at energies 162 and 291 MeV by using two kinds of the microscopic optical potentials (OPs). The first one is the folding OP, where the known nuclear density distributions are used while parameters of the elementary pion-nucleon amplitude of scattering are fitted to the data with the aim to estimate the in-medium effect, when pions are scattered not on the free but on the nuclear bounded nucleons. The analysis given when calculations are made using the local Kisslinger type OP, whose parameters are fitted to the data. The cross sections for both OPs are obtained by solving the Klein-Gordon wave equation. The role of a surface region of potentials is discusses.

Analysis of 6Li+16O elastic scattering using different potentials

Available experimental angular distributions for 6Li elastically scattered from 16O nucleus in the energy range 13.0–50.0 MeV are reanalyzed within the framework of optical potential, double folding optical potential as well as cluster folding potential. Special interest was paid to the cluster folding based on the well-known cluster structure of 6Li. Elastic scattering data for 6Li+16O system plotted as a function of momentum transfer showed that the real Coulomb nuclear interference region independent of the bombarding energy. This structural behavior for the data could be used to define the interaction potential with some certainty and to extract reliable values for the renormalization factors.

Analysis of α+11B elastic and inelastic scattering using microscopic and semi-microscopic representations

In the present study angular distributions of the differential cross section for elastic and inelastic scattering of alpha (α)-particles of 11В nuclei at different bombarding energies have been analyzed in the framework of the optical model (OM) potential. Two OM folding approaches were adopted in order to construct the real part of the α-nucleus potential. First, we generated the semi-microscopic single folding (SF) potential by folding an effective α-nucleon (α-N) interaction over the nuclear matter density of the target (11B) nucleus. In addition, the double folding (DF) approach was employed in order to deduce a microscopic representation of the optical potential by folding an effective density-dependent (DDM3Y) nucleon–nucleon interaction over the matter densities of the colliding nuclei. Successful theoretical predictions of six sets of experimental elastic scattering data have been obtained over the whole measured angular range. However, it was found that introducing real renormalization coefficients (∼0.9–1.6) is essential in order to obtain best fits with data. On the other side, sixteen sets of the inelastic scattering data at several excited states of 11B nucleus were analyzed using the constructed SF and DF deformed potentials. In general, reasonable description of the data is obtained. However underestimated predictions of data were obtained at backward measured angles. The deduced reaction (absorption) cross sections and nuclear deformation lengths were also investigated.

РАСЧЕТ СЕЧЕНИЙ УПРУГОГО РАССЕЯНИЯ 11LI + P C ИСПОЛЬЗОВАНИЕМ ОПТИЧЕСКОГО ФОЛДИНГ-ПОТЕНЦИАЛА

The MPI implementation of the calculation of the microscopic optical potential of nucleon-nucleus scattering within the single folding model has been developed. The folding potential and the corresponding differential cross section of the 11Li + p elastic scattering have been calculated at 62 MeV/nucleon on the heterogeneous cluster "HybriLIT" of the Multifunctional Information and Computational Complex (MICC) of the Laboratory of Information Technologies of JINR. The agreement between experimental data and numerical results for various models of the 11Li density distribution used in the construction of the folding potential is demonstrated

An analysis of cross-sections of 9Be+28Si interaction in the framework of the double-folding model

In this paper the experimental data on the differential cross sections for elastic scattering of 9 Be ions on 28 Si nucleus at the energies of the incident nucleus ranging from 12 to 201.6 MeV were analyzed in the framework of the double folding model using the Paris NN-potential CDM3Y. A good agreement with the experimental angular distributions of differential cross sections for elastic scattering was obtained and the values of the total reaction cross sections were calculated. When the double folding potential was used as real and imaginary parts, no manifestation of the threshold anomaly was detected. The reason for such a behavior of the potential can be explained by the presence of break up and/or transfer channels at low energies.

Role of the dynamical polarization potential in explaining the [formula omitted] system at low energies

In this paper, we have analyzed the elastic scattering data of the α+12C system at 13, 18, 54.1 and 60 MeV incident energies within the framework of the double folding model. We have modified the shape of the real and imaginary parts of the optical potential simultaneously, in the surface region, in order to take into account the effects of the dynamical polarization. With this, we have been able to obtain an improved agreement of the theoretical cross sections with the experimental data. We have also calculated α-cluster states in 16O using the same potential. We have shown that the inclusion of the dynamical polarization potential (DPP) in the bare folding potential provides an improvement also in producing the 16O rotational bands and corresponding excitation energies. Thus, DPP effect is important in explaining the reaction observables of α+12C system as well as the structure of the 16O at low energies

DNA G-quadruplex stability, position and chromatin accessibility are associated with CpG island methylation.

CpG islands (CGI) are genomic regions associated with gene promoters and involved in gene expression regulation. Despite their high CpG content and unlike bulk genomic DNA methylation pattern, these regions are usually hypomethylated. So far, the mechanisms controlling the CGI methylation patterning remain unclear. G-quadruplex (G4) structures can inhibit DNA methyltransferases 1 enzymatic activity, leading to CGI hypomethylation. Our aim was to analyse the association of G4 forming sequences (G4FS) and CGI methylation as well as to determine the intrinsic and extrinsic characteristics of G4FS that may modulate this phenomenon. Using methylation data from human embryonic stem cells (hESCs) and three hESC-derived populations, we showed that hypomethylated CpGs located inside CGI (CGI/CpG) tend to be associated with highly stable G4FS (Minimum free energy≤-30kcal·mol-1 ). The association of highly stable G4FS and hypomethylation tend to be stronger when these structures are located at shorter distances (~<150bp) from GCI/CpGs, when G4FS and CpGs are located within open chromatin and G4FS are inside CGI. Moreover, this association is not strongly influenced by the CpG content of CGI. Conversely, highly methylated CGI/CpG tend to be associated with low stability G4FS. Although CpGs inside CGIs without a G4FS tend to be more methylated, high stability G4FS within CGI neighbourhood were associated with decreased methylation. In summary, our data indicate that G4FS may act as protective cis elements against CGI methylation, and this effect seems to be influenced by the G4FS folding potential, its presence within CGI, CpG distance from G4FS and chromatin accessibility.

De novo Design of Selective Membrane‐Active Peptides by Enzymatic Control of Their Conformational Bias on the Cell Surface

AbstractSelectively targeting the membrane‐perturbing potential of peptides towards a distinct cellular phenotype allows one to target distinct populations of cells. We report the de novo design of a new class of peptide whose ability to perturb cellular membranes is coupled to an enzyme‐mediated shift in the folding potential of the peptide into its bioactive conformation. Cells rich in negatively charged surface components that also highly express alkaline phosphatase, for example many cancers, are susceptible to the action of the peptide. The unfolded, inactive peptide is dephosphorylated, shifting its conformational bias towards cell‐surface‐induced folding to form a facially amphiphilic membrane‐active conformer. The fate of the peptide can be further tuned by peptide concentration to affect either lytic or cell‐penetrating properties, which are useful for selective drug delivery. This is a new design strategy to afford peptides that are selective in their membrane‐perturbing activity.

De novo Design of Selective Membrane-Active Peptides by Enzymatic Control of Their Conformational Bias on the Cell Surface.

Selectively targeting the membrane-perturbing potential of peptides towards a distinct cellular phenotype allows one to target distinct populations of cells. We report the de novo design of a new class of peptide whose ability to perturb cellular membranes is coupled to an enzyme-mediated shift in the folding potential of the peptide into its bioactive conformation. Cells rich in negatively charged surface components that also highly express alkaline phosphatase, for example many cancers, are susceptible to the action of the peptide. The unfolded, inactive peptide is dephosphorylated, shifting its conformational bias towards cell-surface-induced folding to form a facially amphiphilic membrane-active conformer. The fate of the peptide can be further tuned by peptide concentration to affect either lytic or cell-penetrating properties, which are useful for selective drug delivery. This is a new design strategy to afford peptides that are selective in their membrane-perturbing activity.

Analysis of the fusion cross sections for 16,18,20O + 12C systems at low energies

Fusion cross section data for the 16,18,20O + 12C systems at energies near and below the Coulomb barrier are studied within the framework of the optical model. To examine these reactions, the microscopic nucleon–nucleon double folding potentials for real and imaginary parts are found. To make a comprehensive analysis of the effect of neutron-rich systems, we used three different reactions from stable to unstable systems. The microscopic nucleon–nucleon double folding potentials show very good agreement for 16,18,20O + 12C systems with a very weak imaginary potential. Also, we have obtained better agreement by using fully microscopic nucleon–nucleon double folding potentials with the 20O + 12C system’s experimental data than in previous works, but especially at low energies we still have some problems reproducing the 20O + 12C system’s fusion cross section data.

Thermodynamically stable and genetically unstable G-quadruplexes are depleted in genomes across species.

G-quadruplexes play various roles in multiple biological processes, which can be positive when a G4 is involved in the regulation of gene expression or detrimental when the folding of a stable G4 impairs DNA replication promoting genome instability. This duality interrogates the significance of their presence within genomes. To address the potential biased evolution of G4 motifs, we analyzed their occurrence, features and polymorphisms in a large spectrum of species. We found extreme bias of the short-looped G4 motifs, which are the most thermodynamically stable in vitro and thus carry the highest folding potential in vivo. In the human genome, there is an over-representation of single-nucleotide-loop G4 motifs (G4-L1), which are highly conserved among humans and show a striking excess of the thermodynamically least stable G4-L1A (G3AG3AG3AG3) sequences. Functional assays in yeast showed that G4-L1A caused the lowest levels of both spontaneous and G4-ligand-induced instability. Analyses across 600 species revealed the depletion of the most stable G4-L1C/T quadruplexes in most genomes in favor of G4-L1A in vertebrates or G4-L1G in other eukaryotes. We discuss how these trends might be the result of species-specific mutagenic processes associated to a negative selection against the most stable motifs, thus neutralizing their detrimental effects on genome stability while preserving positive G4-associated biological roles.

Pharmacological Chaperones for the Treatment of α-Mannosidosis.

α-Mannosidosis (AM) results from deficient lysosomal α-mannosidase (LAMAN) activity and subsequent substrate accumulation in the lysosome, leading to severe pathology. Many of the AM-causative mutations compromise enzyme folding and could be rescued with purpose-designed pharmacological chaperones (PCs). We found that PCs combining a LAMAN glycone-binding motif based on the 5 N,6 O-oxomethylidenemannojirimycin (OMJ) glycomimetic core and different aglycones, in either mono- or multivalent displays, elicit binding modes involving glycone and nonglycone enzyme regions that reinforce the protein folding and stabilization potential. Multivalent derivatives exhibited potent enzyme inhibition that generally prevailed over the chaperone effect. On the contrary, monovalent OMJ derivatives with LAMAN aglycone binding area-fitting substituents proved effective as activity enhancers for several mutant LAMAN forms in AM patient fibroblasts and/or transfected MAN2 B1-KO cells. This translated into a significant improvement in endosomal/lysosomal function, reverting not only the primary LAMAN substrate accumulation but also the additional downstream consequences such as cholesterol accumulation.

Ab initio folding potentials for nucleon-nucleus scattering based on no-core shell-model one-body densities

Calculating microscopic optical potentials for elastic nucleon-nucleus scattering has already led to large body of work in the past. For folding first-order calculations the nucleon-nucleon (NN) interaction and the one-body density of the nucleus were taken as input to rigorous calculations in a spectator expansion of the multiple scattering series. Based on the Watson expansion of the multiple scattering series we employ a nonlocal translationally invariant nuclear density derived from a chiral next-to-next-to-leading order (NNLO) and the very same interaction for consistent full-folding calculation of the effective (optical) potential for nucleon-nucleus scattering for light nuclei. We calculate scattering observables, such as total, reaction, and differential cross sections as well as the analyzing power and the spin-rotation parameter, for elastic scattering of protons and neutrons from $^4$He, $^{6}$He, $^{12}$C, and $^{16}$O, in the energy regime between 100 and 200~MeV projectile kinetic energy, and compare to available data. Our calculations show that the effective nucleon-nucleus potential obtained from the first-order term in the spectator expansion of the multiple scattering expansion describes experiments very well to about 60 degrees in the center-of-mass frame, which coincides roughly with the validity of the NNLO chiral interaction used to calculate both the NN amplitudes and the one-body nuclear density.

2,4-Dichloro-5-[(N-aryl/alkyl)sulfamoyl]benzoic Acid Derivatives: In Vitro Antidiabetic Activity, Molecular Modeling and In silico ADMET Screening.

Postprandial hyperglycemia can be reduced by inhibiting major carbohydrate hydrolyzing enzymes, such as α-glucosidase and α-amylase which is an effective approach in both preventing and treating diabetes. The aim of this study was to synthesize a series of 2,4-dichloro-5-[(N-aryl/alkyl)sulfamoyl] benzoic acid derivatives and evaluate α-glucosidase and α-amylase inhibitory activity along with molecular docking and in silico ADMET property analysis. Chlorosulfonation of 2,4-dichloro benzoic acid followed by reaction with corresponding anilines/amines yielded 2,4-dichloro-5-[(N-aryl/alkyl)sulfamoyl]benzoic acid derivatives. For evaluating their antidiabetic potential α-glucosidase and α-amylase inhibitory assays were carried out. In silico molecular docking studies of these compounds were performed with respect to these enzymes and a computational study was also carried out to predict the drug-likeness and ADMET properties of the title compounds. Compound 3c (2,4-dichloro-5-[(2-nitrophenyl)sulfamoyl]benzoic acid) was found to be highly active having 3 fold inhibitory potential against α-amylase and 5 times inhibitory activity against α-glucosidase in comparison to standard drug acarbose. Most of the synthesized compounds were highly potent or equipotent to standard drug acarbose for inhibitory potential against α-glucosidase and α-amylase enzyme and hence this may indicate their antidiabetic activity. The docking study revealed that these compounds interact with active site of enzyme through hydrogen bonding and different pi interactions.

The Role of Mg+2 Ion Interactions in Folding of the Twister Ribozyme and PreQ1 Riboswitch Revealed through Umbrella Sampling Combined with Oscillating Chemical Potential Grand Canonical Monte Carlo/Molecular Dynamics Simulations

Ribozymes, RNA molecules that work as enzymes, exhibit self-cleaving properties or catalytic mechanisms for processing of biomolecules. However it is challenging to resolve atomic-details of the folding landscape of ribozymes as they assume the tertiary structures required for catalytic activity. Metal ions, especially Mg+2 ions, are known to neutralize these negatively charged nucleic acids and specifically stabilize RNA tertiary structures. Earlier studies have determined specific binding sites of Mg+2 ions for RNAs, but are limited to folded conformations, such that their role in RNA folding processes is still unclear. Here, we use a computational approach that combines umbrella sampling with oscillating chemical potential Grand Canonical Monte Carlo/Molecular Dynamics (GCMC/MD) simulations to capture the atomic-level details of the intermediate states of RNA folding and identify the ion-RNA interactions that drive the folding pathway. The oscillating excess chemical potential allows for the sampling of Mg+2 ion distributions of the partially folded states of RNA without any bias from initial Mg+2-RNA configurations. We investigate the unfolding of two RNA molecules, the twister ribozyme and preQ1 riboswitch, along reaction coordinates used in experimental studies. We also simulate the ribozymes at different ion concentrations and capture the effect of ions on the folding potentials of mean force. Results reveal the stability of intermediate states and track the ion-mediated conformational changes. Overall, the present study establishes a better understanding of how Mg+2 ion-interactions contribute to RNA folding.

Analysis of 12C+12C scattering using different nuclear density distributions

Elastic 12C+12C angular distributions at three bombarding energies of 102.1, 112.0 and 126.1 MeV were analyzed in the framework of optical model (OM) and compared to the experimental data. The reality of the OM analysis using the double folding potential depends on the chosen nuclear density distributions. In this work, we use two available models of nuclear density distributions obtained from the electron scattering experiments and the density functional theory (DFT). The OM results show that the former gives better description of the 12C nuclear density distribution than the latter. Therefore, the DFT should be worked on for improving the nuclear density description of 12C in the future.

Improved nucleus–nucleus folding potential with a repulsive core due to the change of intrinsic kinetic energy

The change in the internal kinetic energy (KE) of two interacting nuclei grows by increasing their density overlap. We investigated to what extent the double-folding potential based on the density dependent M3Y nucleon–nucleon interaction can be improved by considering this repulsive KE. We adopted the α-decay of , the 24Ne decay of 232U, and the fusion cross section as examples of reactions involving density redistribution. We performed the α and cluster decay calculations based on solving the Schrödinger equation to find the wavefunction and the penetration probability. Upon normalizing the calculated KE by applying the Bohr–Sommerfeld quantization condition, the necessary missed pocket is physically developed in the internal region of the total folding potential. The folding potential improved by considering the pivotal repulsive KE reduced the uncertainty inherent in the decay calculations at small internuclear distances. The calculated fusion cross section is substantially improved and its steep falloff at sub-barrier energies is reasonably reproduced.

Polarization of Nucleons in the Deuteron Stripping Reaction on Nuclei

A general analytical expression has been obtained in the diffraction approximation for the polarization of nucleons arising in the deuteron stripping reaction on nuclei at intermediate energies of the incident particles. A tabulated density distribution of the target nucleus and a realistic wave function of the deuteron with correct asymptotic limits at large internucleon distances were used in the calculations. The nucleon-nucleus phase shifts were calculated in the Glauber formalism using the double folding potential. The calculated angular dependencies for the vector analyzing power $A_{y}$ of the reaction $^{3}\text{He}(\vec{d},p)^{4}\text{He}$ are found to be in satisfactory agreement with the corresponding experimental data.