Hydration Waters Make Up for the Missing Third Hydrogen Bond in the A·T Base Pair
Ontology highlight
ABSTRACT:
SUBMITTER:
PROVIDER: S-EPMC10979491 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:DNA minor-groove-binding compounds have limited biological applications, in part due to problems with sequence specificity that cause off-target effects. A model to enhance specificity has been developed with the goal of preparing compounds that bind to two AT sites separated by G·C base pairs. Compounds of interest were probed using thermal melting, circular dichroism, mass spectrometry, biosensor-SPR, and molecular modeling methods. A new minor groove binder that can strongly and specifically recognize a single G·C base pair with flanking AT sequences has been prepared. This multi-site DNA recognition mode offers novel design principles to recognize entirely new DNA motifs.
| S-EPMC4607563 | biostudies-literature
Project description:Toward the expansion of the genetic alphabet of DNA, we present highly efficient unnatural base pair systems as an artificial third base pair for PCR. Hydrophobic unnatural base pair systems between 7-(2-thienyl)imidazo[4,5-b]pyridine (Ds) and 2-nitro-4-propynylpyrrole (Px) were fine-tuned for efficient PCR, by assessing the amplification efficiency and fidelity using different polymerases and template sequence contexts and modified Px bases. Then, we found that some modifications of the Px base reduced the misincorporation rate of the unnatural base substrates opposite the natural bases in templates without reducing the Ds-Px pairing selectivity. Under optimized conditions using Deep Vent DNA polymerase, the misincorporation rate was extremely low (0.005%/bp/replication), which is close to that of the natural base mispairings by the polymerase. DNA fragments with different sequence contexts were amplified ∼10(10)-fold by 40 cycles of PCR, and the selectivity of the Ds-Px pairing was >99.9%/replication, except for 99.77%/replication for unfavorable purine-Ds-purine motifs. Furthermore, >97% of the Ds-Px pair in DNA survived in the 10(28)-fold amplified products after 100-cycle PCR (10 cycles repeated 10 times). This highly specific Ds-Px pair system provides a framework for new biotechnology.
| S-EPMC3315302 | biostudies-literature
Project description:Interaction of H2O, H2S, H2Se, NH3, PH3, and AsH3 with cations H+, CH3 +, Cu+, Al+, Li+, Na+, and K+ was studied from the energetic and structural viewpoint using B3LYP/6-311++G(d,p) method. The charge transfer from the Lewis bases to the cations reduces lone pair/lone pair (LP/LP) repulsion in H2O, H2S, and H2Se and LP/bond pair (LP/BP) repulsion in NH3, PH3, and AsH3. In parallel, changes in the H-M-H angles (M = O, S, Se, N, P, and As) are observed. The change in the H-M-H angle during the interactions was proportional to the amount of charge transferred from the bases to the cations and electron density (ρ) at the molecule/cation bond critical point. Also, the opposite trend for proton affinities of these two families, that is, NH3 > PH3 > AsH3 and H2O < H2S < H2Se, was interpreted on the basis of LP/BP repulsion in their neutral and protonated forms. Interaction of the Lewis bases with neutral Lewis acids including BeH2, BeF2, and BH3 was studied energetically and structurally. The calculated energies for interactions of H2O and NH3 with BeH2, BeF2, and BH3 are larger than the corresponding values for H2S, H2Se, PH3, and AsH3. This difference was interpreted on the basis of the lower stability of H2O and NH3 because of large LP/LP and LP/BP repulsion in H2O and LP/BP repulsion in NH3.
| S-EPMC6645108 | biostudies-literature
Project description:Gadolinium vibronic sideband luminescence spectroscopy (GVSBLS) is used to probe osmolyte-induced changes in the hydrogen bond strength between first and second shell waters on the surface of free Gd(3+) and Gd(3+) coordinated to EDTA and to structured calcium binding peptides in solution. In parallel, Raman is used to probe the corresponding impact of the same set of osmolytes on hydrogen bonding among waters in the bulk phase. Increasing concentration of added urea is observed to progressively weaken the hydrogen bonding within the hydration layer but has minimal observed impact on bulk water. In contrast, polyols are observed to enhance hydrogen bonding in both the hydration layer and the bulk with the amplitude being polyol dependent with trehalose being more effective than sucrose, glucose, or glycerol. The observed patterns indicate that the size and properties of the osmolyte as well as the local architecture of the specific surface site of hydration impact preferential exclusion effects and local hydrogen bond strength. Correlation of the vibronic spectra with CD measurements on the peptides as a function of added osmolytes shows an increase in secondary structure with added polyols and that the progressive weakening of the hydrogen bonding upon addition of urea first increases water occupancy within the peptide and only subsequently does the peptide unfold. The results support models in which the initial steps in the unfolding process involve osmolyte-induced enhancement of water occupancy within the interior of the protein.
| S-EPMC3354986 | biostudies-literature
Project description:Damage to the genome is implicated in the progression of cancer and stress-induced diseases. DNA lesions exist in low levels, and cannot be amplified by standard PCR because they are frequently strong blocks to polymerases. Here, we describe a method for PCR amplification of lesion-containing DNA in which the site and identity could be marked, copied and sequenced. Critical for this method is installation of either the dNaM or d5SICS nucleotides at the lesion site after processing via the base excision repair process. These marker nucleotides constitute an unnatural base pair, allowing large quantities of marked DNA to be made by PCR amplification. Sanger sequencing confirms the potential for this method to locate lesions by marking, amplifying and sequencing a lesion in the KRAS gene. Detection using the α-hemolysin nanopore is also developed to analyse the markers in individual DNA strands with the potential to identify multiple lesions per strand.
| S-EPMC4667634 | biostudies-literature
Project description:Hydrogen bonding is an interaction of great importance in drug discovery and development as it may significantly affect chemical and biological processes including the interaction of small molecules with other molecules, proteins, and membranes. In particular, hydrogen bonding can impact drug-like properties such as target affinity and oral availability which are critical to developing effective pharmaceuticals, and therefore, numerous methods for the calculation of properties such as hydrogen-bond strengths, free energy of hydration, or water solubility have been proposed over time. However, the accessibility to efficient methods for the predictions of such properties is still limited. Here, we present the development of Jazzy, an open-source tool for the prediction of hydrogen-bond strengths and free energies of hydration of small molecules. Jazzy also allows the visualisation of hydrogen-bond strengths with atomistic resolution to support the design of compounds with desired properties and the interpretation of existing data. The tool is described in its implementation, parameter fitting, and validation against two data sets of experimental hydration free energies. Jazzy is also applied against two chemical series of bioactive compounds to show that hydrogen-bond strengths can be used to understand their structure-activity relationships. Results from the validations highlight the strengths and limitations of Jazzy, and suggest its suitability for interactive design, screening, and machine-learning featurisation.
| S-EPMC10011384 | biostudies-literature
Project description:We employ fully quantum-mechanical molecular dynamics simulations to evaluate the force between two methanes dissolved in water, as a model for hydrophobic association. A stable configuration is found near the methane-methane contact separation, while a shallow second potential minimum occurs for the solvent-separated configuration. The strength and shape of the potential of mean force are in conflict with earlier classical force-field simulations but agree well with a simple hydrophobic burial model which is based on solubility experiments. Examination of solvent dynamics reveals stable water cages at several specific methane-methane separations.
| S-EPMC1815233 | biostudies-literature
Project description:BLUF (blue light sensing using FAD) domains constitute a recently discovered class of photoreceptor proteins found in bacteria and eukaryotic algae, where they control a range of physiological responses including photosynthesis gene expression, photophobia, and negative phototaxis. Other than in well known photoreceptors such as the rhodopsins and phytochromes, BLUF domains are sensitive to light through an oxidized flavin rather than an isomerizable cofactor. To understand the physicochemical basis of BLUF domain photoactivation, we have applied femtosecond transient absorption spectroscopy to the Slr1694 BLUF domain of Synechocystis PCC6803. We show that photoactivation of BLUF domains proceeds by means of a radical-pair mechanism, driven by electron and proton transfer from the protein to the flavin, resulting in the transient formation of anionic and neutral flavin radical species that finally result in the long-lived signaling state on a 100-ps timescale. A pronounced deuteration effect is observed on the lifetimes of the intermediate radical species, indicating that proton movements underlie their molecular transformations. We propose a photoactivation mechanism that involves a successive rupture of hydrogen bonds between a conserved tyrosine and glutamine by light-induced electron transfer from tyrosine to flavin and between the glutamine and flavin by subsequent protonation at flavin N5. These events allow a reorientation of the conserved glutamine, resulting in a switching of the hydrogen-bond network connecting the chromophore to the protein, followed by radical-pair recombination, which locks the glutamine in place. It is suggested that the redox potential of flavin generally defines the light sensitivity of flavin-binding photoreceptors.
| S-EPMC1544145 | biostudies-literature
Project description:We describe the structure in aqueous solution of a DNA duplex containing a base pair that is structurally analogous to A-T but which lacks hydrogen bonds. Base analogues F (a nonpolar isostere of thymine) and Z (a nonpolar isostere of adenine) are paired opposite one another in a 12 base pair duplex. The sequence context is the binding site of recently studied transcription factor hSRY. The Z-F pair has been shown to be replicated surprisingly well and selectively by DNA polymerase enzymes, considering that it is destabilizing and lacks Watson-Crick hydrogen bonds. The enzymatic studies led to the suggestion that part of the functional activity arises because the pair resembles a natural one in geometry. The present results show that, despite the absence of Watson-Crick hydrogen bonds, the Z-F pair structurally resembles an A-T pair in the same context. This lends support to the proposal that shape matching is an important component in replication, and suggests the general utility of using Z-F as a nonpolar replacement for A-T in probing protein-DNA interactions.
| S-EPMC2946154 | biostudies-literature
Project description: Not available
| S-EPMC9829387 | biostudies-literature