Favorable Entropy Change Research Articles

Contrasting behavior of urea in strengthening and weakening confinement effects on polymer collapse.

Biomolecules inhabit a crowded living cell that is packed with high concentrations of cosolutes and macromolecules that result in restricted, confined volumes for biomolecular dynamics. To understand the impact of crowding on the biomolecular structure, the combined effects of the cosolutes (such as urea) and confinement need to be accounted for. This study involves examining these effects on the collapse equilibria of three model 32-mer polymers, which are simplified models of hydrophobic, charge-neutral, and uncharged hydrophilic polymers, using molecular dynamics simulations. The introduction of confinement promotes the collapse of all three polymers. Interestingly, addition of urea weakens the collapse of the confined hydrophobic polymer, leading to non-additive effects, whereas for the hydrophilic polymers, urea enhances the confinement effects by enhancing polymer collapse (or decreasing the polymer unfolding), thereby exhibiting an additive effect. The unfavorable dehydration energy opposes collapse in the confined hydrophobic and charge-neutral polymers under the influence of urea. However, the collapse is driven mainly by the favorable change in polymer-solvent entropy. The confined hydrophilic polymer, which tends to unfold in bulk water, is seen to have reduced unfolding in the presence of urea due to the stabilizing of the collapsed state by urea via cohesive bridging interactions. Therefore, there is a complex balance of competing factors, such as polymer chemistry and polymer-water and polymer-cosolute interactions, beyond volume exclusion effects, which determine the collapse equilibria under confinement. The results have implications to understand the altering of the free energy landscape of proteins in the confined living cell environment.

3-Amide-β-carbolines block the cell cycle by targeting CDK2 and DNA in tumor cells potentially as anti-mitotic agents

β-Carboline alkaloids are natural and synthetic products with outstanding antitumor activity. C3 substituted and dimerized β-carbolines exert excellent antitumor activity. In the present research, 37 β-carboline derivatives were synthesized and characterized. Their cytotoxicity, cell cycle, apoptosis, and CDK2- and DNA-binding affinity were evaluated. β-Carboline monomer M3 and dimer D4 showed selective activity and higher cytotoxicity in tumor cells than in normal cells. Structure-activity relationships (SAR) indicated that the amide group at C3 enhanced the antitumor activity. M3 blocked the A549 (IC50 = 1.44 ± 1.10 μM) cell cycle in the S phase and inhibited A549 cell migration, while D4 blocked the HepG2 (IC50 = 2.84 ± 0.73 μM) cell cycle in the G0/G1 phase, both of which ultimately induced apoptosis. Furthermore, associations of M3 and D4 with CDK2 and DNA were proven by network pharmacology analysis, molecular docking, and western blotting. The expression level of CDK2 was downregulated in M3-treated A549 cells and D4-treated HepG2 cells. Moreover, M3 and D4 interact with DNA and CDK2 at sub-micromolar concentrations in endothermic interactions caused by entropy-driven adsorption processes, which means that the favorable entropy change (ΔS > 0) overcomes the unfavorable enthalpy change (ΔH > 0) and drives the spontaneous reaction (ΔG < 0). Overall, these results clarified the antitumor mechanisms of M3 and D4 through disrupting the cell cycle by binding DNA and CDK2, which demonstrated the potential of M3 and D4 as novel antiproliferative drugs targeting mitosis.

Evaluation of calf thymus DNA binding of newly synthesize five 9 [sbnd]O[sbnd] Imidazolyl alkyl berberine derivative: A comparative multi-spectroscopic and calorimetric study

DNA binding with small molecule plays an important role in the designing of various anticancer drugs with greater efficacy. The five 9-O-imidazolyl alkyl berberine derivatives (BI) of different chain length has been synthesized and fully characterized. The binding study of calf thymus DNA with these newly synthesized berberine derivative was performed using various biophysical techniques. The binding affinity of BI to calf thymus DNA increased with increasing the chain length. The binding constant value obtained from UV–Vis spectral analysis was 1.84x105for BI1, 2.01x105for BI2, 1.51 × 106 for BI3, 3.66 × 106 for BI4, 6.68 × 106. Partial intercalative binding with strong stabilization of the DNA helix was revealed from circular dichroism spectral study and viscosity measurement. From the ITC experiment it was revealed that the bindings of BI1, BI2, BI3, BI4 and BI5 to calf thymus DNA were favoured by a large positive favourable entropy and negative enthalpy change and the highest spontaneity found for BI5. With the increase in chain length the binding was driven by a stronger entropy term with a higher binding constant indicates involvement of hydrophobic force for all these interaction. High binding affinities of calf thymus DNA with berberine-imidazole derivatives might be helpful for new drug design.

Molecular Crowders Can Induce Collapse in Hydrophilic Polymers via Soft Attractive Interactions.

A comprehensive understanding of protein folding and biomolecular self-assembly in the intracellular environment requires obtaining a microscopic view of the crowding effects. The classical view of crowding explains biomolecular collapse in such an environment in terms of the entropic solvent excluded volume effects subjected to hard-core repulsions exerted by the inert crowders, neglecting their soft chemical interactions. In this study, the effects of nonspecific, soft interactions of molecular crowders in regulating the conformational equilibrium of hydrophilic (charged) polymers are examined. Using advanced molecular dynamics simulations, collapse free energies of an uncharged, a negatively charged, and a charge-neutral 32-mer generic polymer are computed. The strength of the polymer-crowder dispersion energy is modulated to examine its effect on polymer collapse. The results show that the crowders preferentially adsorb and drive the collapse of all three polymers. The uncharged polymer collapse is opposed by the change in solute-solvent interaction energy but is overcompensated by the favorable change in the solute-solvent entropy as observed in hydrophobic collapse. However, the negatively charged polymer collapses with a favorable change in solute-solvent interaction energy due to reduction in the dehydration energy penalty as the crowders partition to the polymer interface and shield the charged beads. The collapse of a charge-neutral polymer is opposed by the solute-solvent interaction energy but is overcompensated by the solute-solvent entropy change. However, for the strongly interacting crowders, the overall energetic penalty decreases since the crowders interact with polymer beads via cohesive bridging attractions to induce polymer collapse. These bridging attractions are found to be sensitive to the binding sites of the polymer, since they are absent in the negatively charged or uncharged polymers. These interesting differences in thermodynamic driving forces highlight the crucial role of the chemical nature of the macromolecule as well as of the crowder in determining the conformational equilibria in a crowded milieu. The results emphasize that the chemical interactions of the crowders should be explicitly considered to account for the crowding effects. The findings have implications in understanding the crowding effects on the protein free energy landscapes.

A Phenylboronic Acid-Based Transition State Analogue Yields Nanomolar Inhibition of Mandelate Racemase.

Mandelate racemase (MR) catalyzes the Mg2+-dependent interconversion of (R)- and (S)-mandelate by stabilizing the altered substrate in the transition state (TS) by ∼26 kcal/mol. The enzyme has been employed as a model to explore the limits to which the free energy of TS stabilization may be captured by TS analogues to effect strong binding. Herein, we determined the thermodynamic parameters accompanying binding of a series of bromo-, chloro-, and fluoro-substituted phenylboronic acids (PBAs) by MR and found that binding was predominately driven by favorable entropy changes. 3,4-Dichloro-PBA was discovered to be the most potent inhibitor yet identified for MR, binding with a Kdapp value of 11 ± 2 nM and exceeding the binding of the substrate by ∼72,000-fold. The ΔCp value accompanying binding (-488 ± 18 cal·mol-1 K-1) suggested that dispersion forces contribute significantly to the binding. The pH-dependence of the inhibition revealed that MR preferentially binds the anionic, tetrahedral form of 3,4-dichloro-PBA with a pH-independent Ki value of 5.7 ± 0.5 nM, which was consistent with the observed upfield shift of the 11B NMR signal. The linear free energy relationship between log(kcat/Km) and log(1/Ki) for wild-type and 11 MR variants binding 3,4-dichloro-PBA had a slope of 0.8 ± 0.2, indicating that MR recognizes the inhibitor as an analogue of the TS. Hence, halogen substitution may be utilized to capture additional free energy of TS stabilization arising from dispersion forces to enhance the binding of boronic acid inhibitors by MR.

Engineering the Active Site Lid Dynamics to Improve the Catalytic Efficiency of Yeast Cytosine Deaminase

Conformational dynamics is important for enzyme catalysis. However, engineering dynamics to achieve a higher catalytic efficiency is still challenging. In this work, we develop a new strategy to improve the activity of yeast cytosine deaminase (yCD) by engineering its conformational dynamics. Specifically, we increase the dynamics of the yCD C-terminal helix, an active site lid that controls the product release. The C-terminal is extended by a dynamical single α-helix (SAH), which improves the product release rate by up to ~8-fold, and the overall catalytic rate kcat by up to ~2-fold. It is also shown that the kcat increase is due to the favorable activation entropy change. The NMR H/D exchange data indicate that the conformational dynamics of the transition state analog complex increases as the helix is extended, elucidating the origin of the enhanced catalytic entropy. This study highlights a novel dynamics engineering strategy that can accelerate the overall catalysis through the entropy-driven mechanism.

Water-Mediated attraction between Like-charged species involved in calcium phosphate nucleation

There is overwhelming evidence that the biomineralization pathway involves prenucleation clusters (PNCs). Studies of calcium phosphate precipitation have shown that the thermodynamically favorable pathway to form the PNC identified as calcium triphosphate (Ca(HPO4)34-) includes two stable ion species (CaHPO4, Ca(HPO4)22–). However, the underlying mechanism remains unclear. Here, we reveal that the formation of these three species exhibits extremely distinct thermodynamic mechanisms. In sharp contrast to an entropy-driven Ca2+-HPO42- (CaP1) pairing compensated by unfavorable energy variation, free energy calculations display an energy-dominated association for CaHPO4-HPO42- (CaP2) and Ca(HPO4)22–-HPO42- (CaP3) with a slightly favorable entropy change. Further free energy decompositions demonstrate that the ion-induced favorable entropic and energetic variations are responsible for CaP1 and CaP2 associations, while the solvent-induced energy change accounts for the CaP3 pairing between two species carrying the same charges. In the complete prenucleation process starting from aqueous solution, the solvent-induced energy change initially hinders the CaP1 pairing but eventually makes a favorable contribution to the CaP3 association. Specifically, the enhanced stability and alignment of the hydrated water molecules around the ion species with charges of the same sign lead to the substantial favorable water-induced energy change and thus promote the CaP3 association even without any counterions.

Two Windmill-Shaped Ln18 Nanoclusters Exhibiting High Magnetocaloric Effect and Luminescence

The self-assembly of the high-nuclearity Ln-exclusive nanoclusters is challenging but of significance due to its aesthetically pleasing architectures and far-reaching latent applications in magnetic cooling technologies. Herein, two novel high-nuclearity lanthanide nanoclusters were successfully synthesized under solvothermal conditions, formulated as {[Gd18(IN)20(HCOO)8(μ6-O)(μ3-OH)24(H2O)4]·4H2O}n and {[Eu18(IN)16(HCOO)8(CH3COO)4(μ6-O)(μ3-OH)24(H2O)4]·5H2O}n (abbreviated as Gd18 and Eu18, HIN = isonicotinic acid). Both of them possess novel and exquisite windmill-shaped cationic cores in the family of high-nuclearity Ln-exclusive nanoclusters. Remarkably, the adjacent second building units are interconnected into a three-dimensional (3D) metal-organic framework by IN- ligands. As expected, the abundant existence of GdIII ions endows Gd18 with a favorable magnetic entropy change at 2.0 K for ΔH = 7.0 T (-ΔSmmax = 40.0 J kg-1 K-1), and Eu18 displays the typical luminescence of EuIII ions.

Physical insight into the entropy-driven ion association.

The ion association is widely believed to be dominated by the favorable entropy change arising from the release of water molecules from ion hydration shells. However, no direct thermodynamic evidence exists to validate the reliability and suitability of this view. Herein, we employ complicated free energy calculations to rigorously split the free energy including its entropic and enthalpic components into the water-induced contributions and ion-ion interaction terms for several ion pairs from monatomic to polyatomic ions, spanning the size range from small kosmotropes to large chaotropes (Na+ , Cs+ , Ca2+ , F- , I- , CO3 2- , and HPO4 2- ). Our results successfully reveal that though ion associations are indeed determined by a delicate balance between the favorable entropy variation and the repulsive enthalpy change, the entropy gain dominated by the solvent occurs only for the monatomic ion pairing. The water-induced entropic contribution significantly goes against the ion pairing between polyatomic anion and cation, which is, alternatively, dominated by the favorable entropy from the ion-ion interaction term, due to the configurational arrangement of polyatomic anions involved in ion association. The structural and dynamic analysis demonstrates that the entropy penalty from the water phase is primarily ascribed to the enhanced stability of water molecules around the cation imposed by the incoming anion. Our study successfully provides a fundamental understanding of water-mediated ion associations and highlights disparate lengthscale dependencies of the dehydration thermodynamics on the specific types of ions.

Investigating Substrate Specificity For 6‐Hydroxynicotinate 3‐Monooxygenase (NicC) With Coumalic Acid: Consequences To Catalysis Of Replacing or Removing The Ring Nitrogen

6‐Hydroxynicotinate 3‐monooxygenase (NicC) is a group A flavin dependent monooxygenase (FDM) that catalyzes the regioselective decarboxylative hydroxylation of 6‐HNA into 2,5‐dihydroxypyridine (DHP) with the concomitant oxidation of NADH to NAD+. This enzyme‐catalyzed reaction involves three segments: (1) substrate binding, (2) FAD reduction by NADH, and (3) hydroxylation‐decarboxylation of 6‐HNA through a hydroperoxy‐flavin intermediate. Past studies have shown that NicC can catalyze this reaction with alternate aromatic substrates including 4‐hydroxybenzoic acid (4‐HBA), a substrate analogue with a homocyclic ring (i.e. lacking the ring nitrogen). However, 4‐HBA is bound weakly (355 ± 66 μM) and only 50% of the reaction progresses to substrate hydroxylation, versus hydroperoxy‐flavin degradation to H2O2, suggesting the importance of the ring nitrogen in the coupling efficiency of NicC. To further explore the role of the ring nitrogen, the efficiency of the reaction with coumalic acid (CA) was determined. The NicC‐CA dissociation constant measured by monitoring the change in absorbance at 450nm (flavin) shows that NicC binds CA (Kd = 5 ± 1 μM) 10x more tightly than 6‐HNA (Kd = 58 ± 12 μM). Binding of CA by NicC is an isothermal process (∆H = 0), indicating that it is driven by a favorable change in entropy. Analysis of the reaction products by Q‐TOF MS indicates that NicC catalyzes the decarboxylative hydroxylation of CA into 5‐hydroxy‐2H‐pyrane‐2‐one. However, coupling experiments by HPLC analysis and detection of H2O2 by a fluorescence assay both indicate that the reaction with CA is highly uncoupled with only minor 5‐hydroxy‐2H‐pyrane‐2‐one formation. Steady‐state kinetic analyses show that CA bound to NicC enhances its rate of NADH oxidation 16‐fold (by comparison, 6‐HNA enhances the rate of NicC NADH oxidation 30‐fold). Transient state kinetic analyses by stopped flow under anaerobic conditions to permit single‐turnover kinetics shows that, unlike in the binding of 6‐HNA, the binding of CA does not enable the formation of a charge‐transfer complex prior to FAD reduction. These results indicate that an H‐bond accepting group in the aromatic ring at position 1 is important for establishing the correct conformation of the ES complex to enable effective binding, flavin reduction and, ultimately, substrate hydroxylation.

Exciton-tryptophan coupling pulse behaviour along with corona formation, binding analysis, and interaction study of ZnO nanorod-serum albumin protein bioconjugate.

The bioconjugate of bovine serum albumin (BSA) and zinc oxide nanorods (ZnO NRs) is investigated to explore the behaviour of the tryptophan (Trp)-exciton coupling and corona formation. The pulse like nature of the coupled system between Trp of BSA and exciton of ZnO NRs has been observed after analysis of the optical parameters such as refractive index, susceptibility, and optical dielectric constant. The time constant for tryptophan, exciton surface binding (t1 ) and reorganization (t2 ) are found to be (t1 ) 8 min, 7 min and (t2 ) 150 min, 114.5 min, respectively. The close proximity binding of BSA with ZnO NRs via tryptophan as well as exciton is responsible for bioconjugate formation. The aggregated structure of BSA is observed from small-angle X-ray scattering study in interaction with ZnO NRs. The change in secondary structure and tertiary deformation of the serum protein have been studied from Fourier transform infrared and emission quenching analyses. The number of binding sites (n) signified to the enhancement of the cooperative binding. The binding has been found to be endothermic and favoured using unfavourable positive enthalpy with a favourable entropy change from the result of the isothermal titration calorimetry.

Disentangling contributions to guest binding inside a coordination cage host: analysis of a set of isomeric guests with differing polarities.

Binding of a set of three isomeric guests (1,2-, 1,3- and 1,4-dicyanobenzene, abbreviated DCB) inside an octanuclear cubic coordination cage host H (bearing different external substitutents according to solvent used) has been studied in water/dmso (98 : 2) and CD2Cl2. These guests have essentially identical molecular surfaces, volumes and external functional groups to interact with the cage interior surface; but they differ in polarity with dipole moments of ca. 7, 4 and 0 Debye respectively. In CD2Cl2 guest binding is weak but we observe a clear correlation of binding free energy with guest polarity, with 1,4-DCB showing no detectable binding by NMR spectroscopy but 1,2-DCB having -ΔG = 9 kJ mol-1. In water (containing 2% dmso to solubilise the guests) we see the same trend but all binding free energies are much higher due to an additional hydrophobic contribution to binding, with -ΔG varying from 16 kJ mol-1 for 1,4-DCB to 22 kJ mol-1 for 1,4-DCB: again we see an increase associated with guest polarity but the increase in -ΔG per Debye of dipole moment is around half what we observe in CD2Cl2 which we ascribe to the fact the more polar guests will be better solvated in the aqueous solvent. A van't Hoff analysis by variable-temperature NMR showed that the improvement in guest binding in water/dmso is entropy-driven, which suggests that the key factor is not direct electrostatic interactions between a polar guest and the cage surface, but the variation in guest desolvation across the series, with the more polar (and hence more highly solvated) guests having a greater favourable entropy change on desolvation.

Entropy in the Molecular Recognition of Membrane Protein-Lipid Interactions.

Understanding the molecular driving forces that underlie membrane protein-lipid interactions requires the characterization of their binding thermodynamics. Here, we employ variable-temperature native mass spectrometry to determine the thermodynamics of lipid binding events to the human G-protein-gated inward rectifier potassium channel, Kir3.2. The channel displays distinct thermodynamic strategies to engage phosphatidylinositol (PI) and phosphorylated forms thereof. The addition of a 4'-phosphate to PI results in an increase in favorable entropy. PI with two or more phosphates exhibits more complex binding, where lipids appear to bind two nonidentical sites on Kir3.2. Remarkably, the interaction of 4,5-bisphosphate PI with Kir3.2 is solely driven by a large, favorable change in entropy. Installment of a 3'-phosphate to PI(4,5)P2 results in an altered thermodynamic strategy. The acyl chain of the lipid has a marked impact on binding thermodynamics and, in some cases, enthalpy becomes favorable.

Thermodynamic Analysis for Binding of 4-O-β-tri-N-acetylchitotriosyl Moranoline, a Transition State Analogue Inhibitor for Hen Egg White Lysozyme.

4-O-β-tri-N-acetylchitotriosyl moranoline (GN3M) is a transition-state analogue for hen egg white lysozyme (HEWL) and identified as the most potent inhibitor till date. Isothermal titration calorimetry experiments provided the thermodynamic parameters for binding of GN3M to HEWL and revealed that the binding is driven by a favorable enthalpy change (ΔH° = −11.0 kcal/mol) with an entropic penalty (−TΔS° = 2.6 kcal/mol), resulting in a free energy change (ΔG°) of −8.4 kcal/mol [Ogata et al. (2013) 288, 6,072–6,082]. Dissection of the entropic term showed that a favorable solvation entropy change (−TΔS solv° = −9.2 kcal/mol) is its sole contributor. The change in heat capacity (ΔC p°) for the binding of GN3M was determined to be −120.2 cal/K·mol. These results indicate that the bound water molecules play a crucial role in the tight interaction between GN3M and HEWL.

Phytochelatins as a Dynamic System for Cd(II) Buffering from the Micro- to Femtomolar Range.

Phytochelatins (PCs) are short Cys-rich peptides with repeating γ-Glu-Cys motifs found in plants, algae, certain fungi, and worms. Their biosynthesis has been found to be induced by heavy metals—both biogenic and toxic. Among all metal inducers, Cd(II) has been the most explored from a biological and chemical point of view. Although Cd(II)-induced PC biosynthesis has been widely examined, still little is known about the structure of Cd(II) complexes and their thermodynamic stability. Here, we systematically investigated glutathione (GSH) and PC2–PC6 systems, with regard to their complex stoichiometries and spectroscopic and thermodynamic properties. We paid special attention to the determination of stability constants using several complementary techniques. All peptides form CdL complexes, but CdL2 was found for GSH, PC2, and partially for PC3. Moreover, binuclear species CdxLy were identified for the series PC3–PC6 in an excess of Cd(II). Potentiometric and competition spectroscopic studies showed that the affinity of Cd(II) complexes increases from GSH to PC4 almost linearly from micromolar (log K7.4GSH = 5.93) to the femtomolar range (log K7.4PC4 = 13.39) and additional chain elongation does not increase the stability significantly. Data show that PCs form an efficient system which buffers free Cd(II) ions in the pico- to femtomolar range under cellular conditions, avoiding significant interference with Zn(II) complexes. Our study confirms that the favorable entropy change is the factor governing the elevation of phytochelatins’ stability and illuminates the importance of the chelate effect in shifting the free Gibbs energy.

Preparation of MIL-100 via a novel water-based heatless synthesis technique for the effective remediation of phenoxyacetic acid-based pesticide

An iron-based metal-organic framework (MOF), MIL-100(Fe) has been synthesized by a novel water-based heatless recipe. The physical-chemical qualities of MIL-100(Fe) were examined by X-ray diffraction, Field Emission Scanning Electron Microscopy, Nitrogen adsorption-desorption isotherm, Thermogravimetric Analysis and Fourier Transform Infrared Spectroscopy. With a high specific surface area of 1,893 m2/g, the crystalline MIL-100(Fe) exhibited an extraordinary performance for the adsorptive removal of 2,4-dichlorophenoxyacetic acid (2,4-D) pesticide from the aqueous solution under laboratory and on-site conditions. The adsorption equilibria have been simulated by the nonlinear Langmuir, Freundlich, Sips, Dubinin–Radushkevich, and Redlich–Peterson isotherm models, with a monolayer adsorption capacity for 2,4-D of 858 mg/g. The adsorption kinetics was rapid, with exceeding 50% of the adsorbate loading has been completed within the first 5 min of contact time, and best described by the pseudo-second order kinetic equation. Further analyses with the Bangham, Vermeulen, and intraparticle diffusion models concluded that intraparticle pore diffusion is the controlling mechanism, but it is not the sole rate-limiting step. MIL-100(Fe) retained the adsorptive performance in the 2,4-D loaded tap water and lakewater samples. The profound effects with solution pH and ionic strength on the adsorptive uptake suggested that the prevailing interaction was the electrostatic attraction between the deprotonated 2,4-D and positive-charged MIL-100(Fe). The adsorption process was spontaneous with favorable enthalpy and entropy changes as the thermodynamic driving force. Water stability test illustrated negligible iron leaching from the Fe-MOF. MIL-100(Fe) adsorbent could be reused for at least 5 times, with minor deterioration in the adsorptive uptake via simple solvent stripping. The high adsorptive potential and well-developed porosity, supported by the sustainable preparation methodology, rendered MIL-100(Fe) a promising adsorbent for the effective decontamination of water pollutants.

Kinetic and thermodynamic insights into the inhibitory mechanism of TMG-chitotriomycin on Vibrio campbellii GH20 exo-β-N-acetylglucosaminidase

We investigated the inhibition kinetics of VhGlcNAcase, a GH20 exo-β-N-acetylglucosaminidase (GlcNAcase) from the marine bacterium Vibrio campbellii (formerly V. harveyi) ATCC BAA-1116, using TMG-chitotriomycin, a natural enzyme inhibitor specific for GH20 GlcNAcases from chitin-processing organisms, with p-nitrophenyl N-acetyl-β-d-glucosaminide (pNP-GlcNAc) as the substrate. TMG-chitotriomycin inhibited VhGlcNAcase with an IC50 of 3.0 ± 0.7 μM. Using Dixon plots, the inhibition kinetics indicated that TMG-chitotriomycin is a competitive inhibitor, with an inhibition constant Ki of 2.2 ± 0.3 μM. Isothermal titration calorimetry experiments provided the thermodynamic parameters for the binding of TMG-chitotriomycin to VhGlcNAcase and revealed that binding was driven by both favorable enthalpy and entropy changes (ΔH° = −2.5 ± 0.1 kcal/mol and −TΔS° = −5.8 ± 0.3 kcal/mol), resulting in a free energy change, ΔG°, of −8.2 ± 0.2 kcal/mol. Dissection of the entropic term showed that a favorable solvation entropy change (−TΔSsolv° = −16 ± 2 kcal/mol) is the main contributor to the entropic term.

Ring-in-Ring(s) Complexes Exhibiting Tunable Multicolor Photoluminescence.

One ring threaded by two other rings to form a non-intertwined ternary ring-in-rings motif is a challenging task in noncovalent synthesis. Constructing multicolor photoluminescence systems with tunable properties is also a fundamental research goal, which can lead to applications in multidimensional biological imaging, visual displays, and encryption materials. Herein, we describe the design and synthesis of binary and ternary ring-in-ring(s) complexes, based on an extended tetracationic cyclophane and cucurbit[8]uril. The formation of these complexes is accompanied by tunable multicolor fluorescence outputs. On mixing equimolar amounts of the cyclophane and cucurbit[8]uril, a 1:1 ring-in-ring complex is formed as a result of hydrophobic interactions associated with a favorable change in entropy. With the addition of another equivalent of cucurbit[8]uril, a 1:2 ring-in-rings complex is formed, facilitated by additional ion-dipole interactions involving the pyridinium units in the cyclophane and the carbonyl groups in cucurbit[8]uril. Because of the narrowing in the energy gaps of the cyclophane within the rigid hydrophobic cavities of cucurbit[8]urils, the binary and ternary ring-in-ring(s) complexes emit green and bright yellow fluorescence, respectively. A series of color-tunable emissions, such as sky blue, cyan, green, and yellow with increased fluorescence lifetimes, can be achieved by simply adding cucurbit[8]uril to an aqueous solution of the cyclophane. Notably, the smaller cyclobis(paraquat-p-phenylene), which contains the same p-xylylene linkers as the extended tetracationic cyclophane, does not form ring-in-ring(s) complexes with cucurbit[8]uril. The encapsulation of this extended tetracationic cyclophane by both one and two cucurbit[8]urils provides an incentive to design and synthesize more advanced supramolecular systems, as well as opening up a feasible approach toward achieving tunable multicolor photoluminescence with single chromophores.

Thermodynamics and kinetics of pretilachlor adsorption: Implication to controlled release from organobentonites

To get a further insight into the mechanism of controlled release from organobentonites, thermodynamics and kinetics of pretilachlor adsorption on organobentonites modified with dodecyltrimethyl ammonium chloride (DTMA) was conducted. The structural effects of organobentonites on the interaction with pretilachlor and the diffusion of the herbicide in interlayer space were investigated and related to the sustained release of pretilachlor from organobentonites. The adsorption of pretilachlor was a spontaneous process (ΔG < 0) dominated by hydrophobic interaction with an unfavorable enthalpy (ΔH > 0) and favorable entropy change (ΔS > 0). The entropy change dropped with increasing surfactant loading of organobentonites, corresponding to a decrease in the degree of freedom of pretilachlor molecules due to the enhanced structure order of the surfactant in the interlayer gallery. However, the increase in surfactant loading generally resulted in an enhancement of pretilachlor adsorption due to the reduction of enthalpy change. As compared to the pseudo-first-order model, the pseudo-second-order model fitted better to the kinetics of pretilachlor adsorption on organobentonites, of which the rate constant k2 decreased and level off with increasing surfactant loading, exhibiting a similar trend to the entropy change for pretilachlor adsorption. The release of pretilachlor from organobentonites was predominated by Fickian diffusion, which could be understood from adsorption thermodynamics and kinetics. The time taken for 50% of active ingredient to be released, T50, from organobentonites with DTMA loading level ranged from 40 to 150% of the cation exchange capacity of the bentonite was 6–10.6 times that for the control formulation and exhibited a good linear relationship with the relative value of the adsorption equilibrium constant Ka to the rate constant k2 from pseudo-second-order model.

Structure-thermodynamics-relationships of hepatitis C viral NS3 protease inhibitors

Thermodynamic parameters were determined for structurally-related inhibitors of HCV NS3 protease to assess how binding entropies and enthalpies vary with incremental changes at the P2 and P3 inhibitor subsites. Changing the heterocyclic substituent at P2 from a pyridyl to a 7-methoxy-2-phenyl-4-quinolyl group leads to a 710-fold increase in affinity. Annelating a benzene ring onto a pyridine ring leads to quinoline-derived inhibitors having higher affinities, but the individual enthalpy and entropy contributions are markedly different for each ligand pair. Introducing a phenyl group at C2 of the heterocyclic ring at P2 uniformly leads to higher affinity analogs with more favorable binding entropies, while adding a methoxy group at C7 of the quinoline ring at P2 provides derivatives with more favorable binding enthalpies. Significant enthalpy/entropy compensation is observed for structural changes made to inhibitors lacking a 2-phenyl substituent, whereas favorable changes in both binding enthalpies and entropies accompany structural modifications when a 2-phenyl group is present. Overall, binding energetics of inhibitors having a 2-phenyl-4-quinolyl group at P2 are dominated by entropic effects, whereas binding of the corresponding norphenyl analogs are primarily enthalpy driven. Notably, the reversal from an entropy driven association to an enthalpy driven one for this set of inhibitors also correlates with alternate binding modes. When the steric bulk of the side chain at P3 is increased from a hydrogen atom to a tert-butyl group, there is a 770-fold improvement in affinity. The 30-fold increase resulting from the first methyl group is solely the consequence of a more favorable change in entropy, whereas subsequent additions of methyl groups leads to modest increases in affinity that arise primarily from incremental improvements in binding enthalpies accompanied with smaller favorable entropic contributions.