Decrease In pKa Research Articles

Anomalous proton transfer of a photoacid HPTS in nonaqueous reverse micelles.

The proton transfer reaction is one of the fundamental chemical reactions where the reaction dynamics strongly depend on solvent properties such as acidity or basicity. A photoacid 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS) shows a sharp decrease of pKa (7.7 → 0.5) upon photoexcitation, and the excited-state proton transfer (ESPT) occurs with ultrafast time constants of 2.5 and 89 ps in bulk aqueous solution. However, the two-step proton transfers via the contact ion pair formation and the proton diffusion are strongly limited inside the nanopools of reverse micelles (RMs). The confinement in small RMs strongly impeded the proton transfer reactions. In this work, we report the ESPT of HPTS confined in methanol-in-oil RMs by steady-state and time-resolved electronic spectroscopy. Interestingly, HPTS shows substantial deprotonation in the excited state only in small RMs, while the ESPT of HPTS does not occur in bulk methanol solution due to the low basicity of aliphatic alcohols. The kinetic analysis of time-resolved fluorescence and transient absorption measurements will compare the proton transfer dynamics of HPTS in the water-in-oil and methanol-in-oil RMs. The ESPT of photoacids, especially in the nonaqueous RMs, can be crucial in understanding many important chemical reactions involving proton transfer in the confined environments of cells and membranes.

Anions and Cations Affect Amino Acid Dissociation Equilibria via Distinct Mechanisms.

Salts reduce the pKa of weak acids by a mechanism sensitive to ion identity and concentration via charge screening of the deprotonated state. In this study, we utilize constant pH molecular dynamics simulations to understand the molecular mechanism behind the salt-dependent dissociation of aspartic acid (Asp). We calculate the pKa of Asp in the presence of a monovalent salt and investigate Hofmeister ion effects by systematically varying the ionic radii. We observe that increasing the anion size leads to a monotonic decrease in Asp pKa. Conversely, the cation size affects the pKa nonmonotonically, interpretable in the context of the law of matching water affinity. The net effect of salt on Asp acidity is governed by an interplay of solvation and competing ion interactions. The proposed mechanism is rather general and can be applicable to several problems in Hofmeister ion chemistry, such as pH effects on protein stability and soft matter interfaces.

Polysaccharide-based polyampholyte complex formation: Investigating the role of intra-chain interactions

The difference in inter-chain and intra-chain electrostatic attraction was investigated in polyelectrolyte and polyampholyte electrostatic complex formation. Three polymers with similar backbone molecular structures including chitosan (Ch) polycation, carboxymethyl cellulose (CMCe) polyanion, and carboxymethyl chitosan (CMCh) polyampholyte were used for this purpose. The turbidimetric, water content, and rheological measurements for polyampholyte self-complex showed more dependence on the ionic strength rather than the polyelectrolyte one. The degree of dissociation (α), dissociation constant (pKa), and intrinsic persistence length were calculated by applying the Katchalsky-Lifson model to potentiometric data. We studied the gyration radii as a function of Debye length and observed the polyampholyte chain contractions due to the intra-chain electrostatic attractions, which minimize the entropic gain of the inter-chain complex formation. This is in accordance with the decrease in pKa by αc for CMCh which is the opposite of that for the Ch and CMCe samples. We also found that the polyampholyte has less intrinsic and electrostatic persistence length compared with both polyanion and polycation with similar chain structures indicating the impact of the inter-chain electrostatic interaction on the complex properties. This study deepens our insight about the behavior of CMCh and the nature of difference between CMCh and Ch/CMCe electrostatic complexes.

Interaction between collision cascades and nanocrack in hcp zirconium by molecular dynamics simulations

In this work, molecular dynamics simulations are performed to investigate the interaction between the collision cascades and nanocrack in hcp zirconium. When the thermal spike overlaps with the nanocrack, the collision cascades will induce the healing of the nanocrack. Higher PKA energy leads to higher degree of crack healing at the same separation distance between PKA and nanocrack. The PKA velocity direction changes the fraction of atoms entering the crack by influencing the shape and distribution of the thermal spike. Furthermore, both Zr #3 and #2 potentials show that the degree of crack healing drops as the distance between the nanocrack and PKA decreases. In particular, collision cascades induce the transformation of nanocrack in the basal plane into prismatic vacancy loop is captured due to the interaction between thermal spike with nanocrack. Lastly, the pre-existing nanocrack may induce cascade splitting of hcp Zr. This work provides a mechanistic understanding of the interaction between the nanocrack and irradiation damages in Zr and other hcp metals.

Coordination-Induced Weakening of a C(sp3)-H Bond: Homolytic and Heterolytic Bond Strength of a CH-Ni Agostic Interaction.

The scission of a C(sp3)-H bond to form a new metal-alkyl bond is a fundamental step in coordination chemistry and catalysis. However, the extent of C-H bond weakening when this moiety interacts with a transition metal is poorly understood and quantifying this phenomenon could provide insights into designing more efficient C-H functionalization catalysts. We present a nickel complex with a robust adamantyl reporter ligand that enables the measurement of C-H acidity (pKa) and bond dissociation free energy (BDFE) for a C(sp3)-H agostic interaction, showing a decrease in pKa by dozens of orders of magnitude and BDFE decrease of about 30 kcal/mol upon coordination. X-ray crystallographic data is provided for all molecules, including a distorted square planar NiIII metalloradical and "doubly agostic" NiII(κ2-CH2) complex.

Size-dependent dissociation of surface hydroxyl groups of silica in aqueous solution

The size-dependence of surface hydroxyl dissociation of solid nanoparticles dispersed in aqueous solutions is a basic colloidal interface phenomenon, but there is no model to describe this phenomenon. In this work, nine amorphous silica samples with different radii (r, 6–196 nm) were chosen as model particles, and their effective surface hydroxyl density (Nseff) and dissociation equilibrium constants (Ka) were determined using acid-base titration, showing an obvious size-dependence. With the decrease of r, the Nseff (mol/m2) and pKa all decrease. The decrease of pKa indicates an enhanced dissociation tendency of surface hydroxyls. Two size-dependent models relating Nseff and Ka separately with r were developed, predicting that both lnNseff and pKa decrease linearly with an increase in 1/r. The model equations can well describe the size-dependent data of Nseff and Ka of silica particles. The characteristic parameters Nseff, apparent pKa, and intrinsic pKa corresponding to flat surfaces (r → ∞) for silica particles are estimated to be 9.12 μmol/m2 (or 5.49 sites/nm2), 9.85, and 8.99, respectively. The size-effect on Nseff and Ka becomes obvious when r < 40 nm. This work deepens the understanding of the size-dependent solid/liquid interface phenomena.

Experimental and Theoretical Characterization of Ultrafast Water-Soluble Photochromic Photoacids.

UV-visible transient absorption spectroscopy and quantum mechanical simulations are combined to elucidate the photochemical mechanism of two metastable merocyanine/spiropyran photoacids, 2-[(E)-2-(2-hydroxyphenyl)ethenyl]-3,3-dimethyl-1-(3-sulfopropyl)-3H-indol-1-ium (phenylhydroxy-MCH) and 2-[(E)-2-(1H-indazol-7-yl)ethenyl]-3-(3-sulfopropyl)-1,3-benzothiazol-3-ium (indazole-MCH). Transient absorption spectra demonstrate that trans-acid isomerization to the cis form results in deprotonation on a picosecond time scale. Ring closure to form spiropyran follows promptly from the appropriate conformation or follows at longer time delays (≫3.5 ns) following a barrier crossing for single-bond isomerization to the appropriate conformation. Consistent with the results of Berton et al. [ Chem. Sci. 2020, 11, 8457-8468] , we find that cis-phenylhydroxy-MCH is a stronger acid than trans-phenylhydroxy-MCH. The decrease in pKa upon isomerization is further investigated to benchmark quantum chemical methods for their accuracy. Calculations were performed with nine levels of theory including continuum solvent models and explicit water. The calculations are not sufficient to describe the ΔpKa following isomerization of these photoacids, and more work is necessary to properly evaluate the physical basis for the acidity of the cis photoacids.

Tyrosine, cysteine, and proton coupled electron transfer in a ribonucleotide reductase-inspired beta hairpin maquette.

Tyrosine residues act as intermediates in proton coupled electron transfer reactions (PCET) in proteins. For example, in ribonucleotide reductase (RNR), a tyrosyl radical oxidizes an active site cysteine via a 35 Å pathway that contains multiple aromatic groups. When singlet tyrosine is oxidized, the radical becomes a strong acid, and proton transfer reactions, which are coupled with the redox reaction, may be used to control reaction rate. Here, we characterize a tyrosine-containing beta hairpin, Peptide O, which has a cross-strand, noncovalent interaction between its single tyrosine, Y5, and a cysteine (C14). Circular dichroism provides evidence for a thermostable beta-turn. EPR spectroscopy shows that Peptide O forms a neutral tyrosyl radical after UV photolysis at 160 K. Molecular dynamics simulations support a phenolic/SH interaction in the tyrosine singlet and radical states. Differential pulse voltammetry exhibits pH dependence consistent with the formation of a neutral tyrosyl radical and a pKa change in two other residues. A redox-coupled decrease in cysteine pKa from 9 (singlet) to 6.9 (radical) is assigned. At pD 11, picosecond transient absorption spectroscopy after UV photolysis monitors tyrosyl radical recombination via electron transfer (ET). The ET rate in Peptide O is indistinguishable from the ET rates observed in peptides containing a histidine and a cyclohexylalanine (Cha) at position 14. However, at pD 9, the tyrosyl radical decays via PCET, and the decay rate is slowed, when compared to the histidine 14 variant. Notably, the decay rate is accelerated, when compared to the Cha 14 variant. We conclude that redox coupling between tyrosine and cysteine can act as a PCET control mechanism in proteins.

Brønsted-Acid-Catalyzed Exchange in Polyester Dynamic Covalent Networks.

The effect of catalyst strength on polyester-alcohol dynamic covalent exchange was systematically studied using Brønsted acids and a low-Tg poly(4-methylcaprolactone) vitrimer formulation. Relaxation times, activation energies, and Arrhenius prefactors are correlated with pKa. Strong protic acids induce facile network relaxation at 25 °C on the order of 104-105 s, significantly faster than Lewis acid alternatives that function only above 100 °C. Activation energies span 49-67 kJ/mol and increase as pKa decreases. The opposite trend is observed with the Arrhenius prefactor. We anticipate that the quantitative understanding of Brønsted acid effects disclosed herein will be of utility in future studies that exploit acid-catalyzed dynamic covalent bond exchange.

PKA-CREB-BDNF signaling pathway mediates propofol-induced long-term learning and memory impairment in hippocampus of rats

Studies have found that propofol can induce widespread neuroapoptosis in developing brains, which leads to cause long-term learning and memory abnormalities. However, the specific cellular and molecular mechanisms underlying propofol-induced neuroapoptosis remain elusive. The aim of the present study was to explore the role of PKA-CREB-BDNF signaling pathway in propofol-induced long-term learning and memory impairment during brain development. Seven-day-old rats were randomly assigned to control, intralipid and three treatment groups (n = 5). Rats in control group received no treatment. Intralipid (10%, 10 mL/kg) for vehicle control and different dosage of propofol for three treatment groups (50, 100 and 200 mg/kg) were administered intraperitoneally. FJB staining, immunohistochemistry analysis for neuronal nuclei antigen and transmission electron microscopy were used to detect neuronal apoptosis and structure changes. MWM test examines the long-term spatial learning and memory impairment. The expression of PKA, pCREB and BDNF was quantified using western blots. Propofol induced significant increase of FJB-positive cells and decrease of PKA, pCREB and BDNF protein levels in the immature brain of P7 rats. Using the MWM test, propofol-treated rats demonstrated long-term spatial learning and memory impairment. Moreover, hippocampal NeuN-positive cell loss, long-lasting ultrastructural abnormalities of the neurons and synapses, and long-term down-regulation of PKA, pCREB and BDNF protein expression in adult hippocampus were also found. Our results indicated that neonatal propofol exposure can significantly result in long-term learning and memory impairment in adulthood. The possible mechanism involved in the propofol-induced neuroapoptosis was related to down-regulation of PKA-CREB-BDNF signaling pathway.

Fuzi and Banxia Combination, Eighteen Antagonisms in Chinese Medicine, Aggravates Adriamycin-Induced Cardiomyopathy Associated with PKA/β2AR-Gs Signaling.

Aconite Lateralis Radix Praeparata (Fuzi) and Pinelliae Rhizoma (Banxia) are a combination often used to treat cardiovascular diseases in ancient and modern clinical practice. However, eighteen antagonisms based on traditional Chinese medicine (TCM) theory often abided against such combination therapy. Therefore, exploring whether coadministration of the two herbs can be used in adriamycin- (ADR-) induced cardiomyopathy and clarifying the potential mechanism could help to guide its clinical application. Echocardiography experiments revealed that either Fuzi, Banxia, or their combination had effect on ADR-induced heart dysfunction, while high dose Fuzi exerted positive inotropic effect associated with restored PKA levels. Moreover, low dose Fuzi significantly reduced QT/QTc prolongation, inhibited cardiac apoptosis, and upregulated protein expression of PKA. However, combination of Fuzi and Banxia greatly aggravated QT/QTc prolongation and cardiomyocyte apoptosis in ADR rats compared with each drug alone, which was accompanied by a marked decrease in PKA, pSer346 levels. Similarly, Banxia alone treatment promoted cardiac apoptosis and downregulated protein levels of PKA and pSer346. Additionally, high dose Fuzi treatment also produced proapoptotic effect. Taken together, our study has provided the first direct evidence that combination of Fuzi, a positive inotropic agent, with Banxia promoted cardiac apoptosis in an ADR induced rat model of cardiomyopathy, which may be associated with suppression of PKA/β2AR-Gs signaling. This study also provides scientific language for better understanding of the risks and limitations of combination of Fuzi and Banxia in clinical applications.

Photoactivation of the BLUF Protein PixD Probed by the Site-Specific Incorporation of Fluorotyrosine Residues.

The flavin chromophore in blue-light-using FAD (BLUF) photoreceptors is surrounded by a hydrogen bond network that senses and responds to changes in the electronic structure of the flavin on the ultrafast time scale. The hydrogen bond network includes a strictly conserved Tyr residue, and previously we explored the role of this residue, Y21, in the photoactivation mechanism of the BLUF protein AppABLUF by the introduction of fluorotyrosine (F-Tyr) analogues that modulated the pKa and reduction potential of Y21 by 3.5 pH units and 200 mV, respectively. Although little impact on the forward (dark- to light-adapted form) photoreaction was observed, the change in Y21 pKa led to a 4000-fold increase in the rate of dark-state recovery. In the present work we have extended these studies to the BLUF protein PixD, where, in contrast to AppABLUF, modulation in the Tyr (Y8) pKa has a profound impact on the forward photoreaction. In particular, a decrease in Y8 pKa by 2 or more pH units prevents formation of a stable light state, consistent with a photoactivation mechanism that involves proton transfer or proton-coupled electron transfer from Y8 to the electronically excited FAD. Conversely, the effect of pKa on the rate of dark recovery is markedly reduced in PixD. These observations highlight very significant differences between the photocycles of PixD and AppABLUF, despite their sharing highly conserved FAD binding architectures.

Contrasting pK a Shifts in Cucurbit[7]uril Host-Guest Complexes Governed by an Interplay of Hydrophobic Effects and Electrostatic Interactions.

Cucurbit[7]uril inclusion complexes with guests bearing dimethylamino groups show the expected upward pKa shifts, whereas their diethylamino counterparts display a decrease in pKa due to the preferential stabilization of the unprotonated form. These results identify the diethylamino group as the substituent of choice to avoid receptor-assisted protonation of guest molecules and present new evidence for the role of the hydrophobic effect as a driving force in cucurbituril complexation.

PK(a) of a Proton-Conducting Water Chain in Photosystem II.

Recent high-resolution crystal structures of the water-oxidizing enzyme photosystem II (PSII) show that O4 of the catalytic Mn4CaO5 cluster forms an H-bond with a water molecule W539, which belongs to a chain of water molecules (O4-water chain). Oxidation of Mn4CaO5 to S1 resulted in elongation of the O-H bonds and decrease in pKa(O-H/O(-)) in the [O4-H···OW539-H···OW538-H···OW393] region along the O4-water chain. In S1, removal of all water molecules from the O4-water chain, except W539, resulted in a significant pKa upshift at O4; this suggests that the proton-conducting water chain serves as a conducting media for protons and significantly decreases the donor pKa, leading to a downhill proton transfer. The absence of a corresponding proton-conducting channel is disadvantageous for release of protons from the proton-releasing site, as in the case of O5 that has no H-bond partner.

Temperature dependence of interfacial structures and acidity of clay edge surfaces

In the pursuit of a microscopic understanding of the effects of temperature on the surface reactivity of clay minerals, we conducted first principles molecular dynamics (FPMD) simulations to study the interfacial structures and acidity of clay edge surfaces at elevated temperatures. The common edge surfaces ((010) and (110) types) of phyllosilicates were investigated at 348K and 423K, and the results were compared with those previously derived at ambient conditions. We found that the stable surface sites are the same as at ambient conditions, including Al(OH2)2 (6-fold Al), Al(OH2) (5-fold Al) and Si(OH) on the (010) facet, and Al(OH2), Al(OH)Si and Si(OH) on the (110) surface. The FPMD-based vertical energy gap technique was applied to compute the acidity constants of edge sites and the resulting pKa values show a decreasing trend with temperature. The results demonstrate that although changes in the point of zero charge of the entire material are insignificant up to 348K, the decrease in surface pKa can be 3pKa units, while it can be as large as 6pKa units up to 423K. The derived interface structures and pKa values can be used in future experimental and modeling research, e.g., in interpreting experiments and predicting the surface complexation of metal cations and organics. This study therefore provides a physical basis for investigating the interfacial processes of clay minerals in environments that experience elevated P–T conditions, such as sedimentary basins and geological nuclear waste repositories.

Influence of organic acid on the thermal behavior of dimethyl sulfoxide

Dimethyl sulfoxide (DMSO) has been extensively used as a solvent because of its high-performance characteristics. However, there have been accidents when DMSO has been used in some chemical processes (Lam et al. in J Therm Anal Calorim 85:25–30, 2006; http://riscad.db.aist.go.jp/PHP_EN/index.php). Although the decomposition mechanism of DMSO under acidic conditions is known (Santosusso et al. in Tetrahedron Lett 48:4255–4258, 1974), the number of studies about thermal behavior of DMSO under acidic condition is not large. The purpose of this investigation is to understand the decomposition thermal behavior of DMSO under acidic conditions. Thermal analysis using an accelerating rate calorimeter (ARC) was carried out with acids chosen for their acid dissociation degree constant (pKa), which is a typical parameter of acid strength. ARC data show that the self-heat rate increased and the exothermic onset temperature decreased with decreasing pKa. Additionally, the exothermic onset temperature and pKa had good linear correlation. To verify the initial exothermic reaction, differential scanning calorimetry (DSC) analysis was carried out. DSC results showed that the exothermic onset temperature was due to decomposition of DMSO. The activation energy of the decomposition reaction was calculated from the ARC results (self-heat rate). Our data indicate that the activation energy of the decomposition reaction decreased with decreasing pKa. Therefore, thermal hazards of DMSO increase with the decrease in pKa, with good linear correlation.

Acids, Bases, and Salts in Mixed-Aqueous Solvents

The dependence of the dissociation constants of acids and bases and their tendency to form salts upon solvent composition in mixed-aqueous solvents are reviewed, along with the activities of the solvent components. The acid–base equilibria are dominated by preferential solvation of the ions by water molecules in the mixtures, compounded by the very high water activities across most of the solvent composition range; the neutral components are normally preferentially solvated by the organic component of the solvent mixture. Neutral acids, such as carboxylic acids and phenols, show only modest increases in pKa (1–2 pK units) in solvent mixtures containing up to 60–70 wt % organic component; thereafter is a much steeper, solvent-dependent increase to the value in the pure organic solvent. Cationic acids, such as protonated amines, anilines, and pyridines, display a universal decrease in pKa (∼1 pK unit) up until around 80 wt % organic solvent, almost independent of the nature of the base or the solvent; beyon...

Phosphatidylserine, a Lipid Present at the Outer Membrane Leaflet of Cancer Cells, Hinders the Insertion of pHLIP, a Potential Cancer Cell Marker

The pH-Low Insertion Peptide (pHLIP) has shown the ability to insert into membranes when acidic conditions are present. pHLIP can be found in three different states: a random coil in pH 8 solution devoid of lipids (state I), a surface bound form when lipids are present (state II), and a transmembrane helix in acidic conditions (state III). From this ability of insertion based on pH, pHLIP has been shown to effectively target diseases in which the extracellular pH of the tissue has become acidic. Cancer is an example of such a disease, and it has been shown that pHLIP can target cancerous cells. One concern with this targeting is that some cancerous cells are known to display phosphatidylserine (PS) in the outer leaflet of the their plasma membranes, as opposed to normal cells. However, little is known about how pHLIP's tumor targeting is influenced by this increased PS content. Here, we study how pHLIP properties are influenced by the presence of PS by using phosphatidylcholine (PC) large unilamellar vesicles (LUV's) that contain PS. Circular dichroism data shows that the characteristic three states are maintained in the presence of PS. Our results show that pHLIP has higher affinity to PC than to PS. We also found that when LUV's contain PS, the insertion pKa decreases compared to LUV's only containing PC with a midpoint at 0.9±0.4 percent. This decrease in insertion pKa might limit pHLIP's targeting of mildly acidic tumors. We added sodium chloride to screen any electrostatic repulsion; however, no change in the pKa was observed. This suggests that the effect of PS on the binding and insertion of pHLIP is not merely due to electrostatic repulsion.

Faster photodegradation rate and higher dioxin yield of triclosan induced by cationic surfactant CTAB

Triclosan has received extensive attention as it has been frequently detected in the aquatic environment. Photolysis was found to be a major pathway governing the fate of triclosan in the aquatic environment. However, the effects of surfactants that usually coexist with triclosan, on the photodegradation of triclosan, are largely unknown. In this study, the effects of selected surfactants on the photodegradation of triclosan were investigated experimentally. The results show that anionic sodium dodecyl benzene sulfonate, sodium dodecyl sulfate and neutral polyoxyethylene (20) sorbitan monooleate inhibit the photolysis of triclosan, whereas cationic cetyltrimethylammonium bromide (CTAB) significantly accelerates the photodegradation rate of triclosan. The interactions between the hydrophilic group of CTAB and anionic triclosan lead to the apparent decrease of pKa of triclosan from 8.4 to 6.1, which increase the fraction of anionic triclosan from 4% to 89% in neutral solution. A red shift in the UV–VIS absorption spectrum is exhibited, thus leading to the increased photodegradation rate of triclosan. The accelerations caused by CTAB were observed under xenon lamp and Hg lamp irradiances, as well as under natural sunlight. Effect of CTAB demonstrated pH dependence with significantly enhancement under pH 5∼9 and inhibition at pH=3. The presence of CTAB also increased the yield of 2,8-dichlorodibenzo-p-dioxin from the photolysis of triclosan about 7 times at pH=7.

Isomeric Mono-, Di-, and Tri-Bromobenzo-1H-Triazoles as Inhibitors of Human Protein Kinase CK2α

To further clarify the role of the individual bromine atoms of 4,5,6,7-tetrabromotriazole (TBBt), a relatively selective inhibitor of protein kinase CK2, we have examined the inhibition (IC50) of human CK2α by the two mono-, the four di-, and the two tri- bromobenzotriazoles relative to that of TBBt. Halogenation of the central vicinal C(5)/C(6) atoms proved to be a key factor in enhancing inhibitory activity, in that 5,6-di-Br2Bt and 4,5,6-Br3Bt were almost as effective inhibitors as TBBt, notwithstanding their marked differences in pKa for dissociation of the triazole proton. The decrease in pKa on halogenation of the peripheral C(4)/C(7) atoms virtually nullifies the gain due to hydrophobic interactions, and does not lead to a decrease in IC50. Molecular modeling of structures of complexes of the ligands with the enzyme, as well as QSAR analysis, pointed to a balance of hydrophobic and electrostatic interactions as a discriminator of inhibitory activity. The role of halogen bonding remains debatable, as originally noted for the crystal structure of TBBt with CK2α (pdb1j91). Finally we direct attention to the promising applicability of our series of well-defined halogenated benzotriazoles to studies on inhibition of kinases other than CK2.