The Journal of Physical Chemistry B最新文献

Chemical inhibitors bind to enzymes, thereby inhibiting their catalytic activity. While many enzymes catalyze reactions with a single substrate, others, like DNA polymerase, can act on multiple related substrates. Substrate-selective inhibitors (SSIs) target these multisubstrate enzymes to modulate their specificity. Although SSIs hold promise as therapeutics, our theoretical understanding of how different inhibitors influence enzyme specificity remains limited. In this study, we examine enzyme selectivity within kinetic networks corresponding to known inhibition mechanisms. We demonstrate that competitive and uncompetitive inhibitors do not affect substrate specificity, regardless of rate constants. In contrast, noncompetitive and mixed inhibition can alter specificity and can lead to nonmonotonic responses to the inhibitor. We show that mixed and noncompetitive inhibitors achieve substrate-selective inhibition by altering the effective free-energy barriers of product formation pathways that are enabled by the inhibitor’s presence. We then apply this framework to the Sirtuin-family deacylase SIRT2, showing that the suicide inhibitor thiomyristoyl lysine (TM) cannot influence substrate specificity unless there is a direct substrate exchange reaction or biochemical constraints are relaxed. These findings provide insights into engineering systems where cofactor binding modulates metabolic flux ratios.

Cold crystallization, an exothermic phase transition upon heating of a glassy state, is of interest in heat storage materials. While such behavior is common in polymers, small-molecule systems have also been investigated. Herein, we report a semiflexible macrocyclic compound composed of four silyl ether units and aromatic linkers that exhibits distinct cold crystallization. A key for the molecular design is semiflexible silyl ether units significantly affecting the macrocyclic shape. Differential scanning calorimetry revealed the formation of a glassy state by melt quenching, followed by exothermic crystallization. Powder X-ray diffraction indicated that the molecular conformation and packing in the crystals after cold crystallization are similar to those of solution-grown crystals. In contrast, a biphenylene-bridged macrocycle and a reference compound with a nonmacrocyclic structure did not show this behavior. These results suggest that a macrocyclic structure with suitable conformational mobility may help in the design of small molecular systems showing cold crystallization as heat storage materials.

The ability of alcohols to perturb the structure and function of membrane bilayers and membrane proteins has made them indispensable in the pharmaceutical and biochemical industry. In the present study, we delineate the bilayer-modifying potency of trifluoroethanol (TFE), a fluorinated analogue of widely used ethanol (EtOH), toward biomimetic lipid membranes composed of pure 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and POPC/cholesterol (POPC/CHOL) lipids using experimental techniques and atomistic molecular dynamics simulations. Our field emission scanning electron microscopy results show the appearance of small particles on the surface of POPC liposome in the presence of 60 v/v% EtOH or TFE, which is otherwise smooth, indicating alcohol-mediated structural modification in the liposome. Dynamic light scattering measurements reveal liposome enlargement at the lower alcohol concentrations and the presence of smaller globules at high concentrations of TFE. The simulation results reveal that the POPC bilayer with TFE suffers the highest degree of perturbation (complete rupture) beyond 50 v/v% concentration, followed by POPC/CHOL-TFE, POPC-EtOH systems, and binary POPC/CHOL bilayer with ethanol partially retaining its bilayer structure at a given concentration. Lipid tail order parameters reveal that TFE induces more disorder in lipids than EtOH for both the POPC and POPC/CHOL systems. Density profiles along the bilayer normal show the loss of bilayer structure with increasing alcohol concentration, with TFE mediating a higher degree of structural disruption at the same concentrations. The higher detrimental impact of TFE on lipid bilayers is attributed to extensive H-bonding and stronger attractive nonpolar interaction between lipid and TFE molecules, leading to weaker lipid–lipid interaction in the presence of TFE and exceptionally high TFE–TFE electrostatic repulsion when compared to its nonfluorinated counterpart.

The foundation for the efficient utilization of potassium resources in Salt Lake brine is to reveal the structural characteristics of the solution, analyze the crystallization behavior process, and its correlation. This study investigated ionic hydration and binding structures in K₂SO₄–MgSO₄ mixed solutions using synchrotron X-ray scattering. Meanwhile, the crystallization behavior of mixed solution droplets was further studied using in situ Raman spectroscopy technology. Research has shown that as the mass fraction of MgSO₄ increases, the hydrogen bond network structure is disrupted in the solution. In the mixed solution, Mg²⁺ competes with K⁺ for SO₄^2–, promoting the transformation of the K⁺–SO₄^2– binding form from a bidentate contact ion pair to a monodentate contact ion pair, forming multi-ion clusters such as K⁺–SO₄^2––Mg²⁺. Under low humidity (RH < 40%), the droplets form a colloidal structure due to Mg²⁺–SO₄^2– chain MCIP, resulting in a 60–92% decrease in water loss rate (k = 0.0059–0.0179 s^–1) compared to pure K₂SO₄ (k = 0.0741 s^–1). In addition, the colloidal interfacial layer in the mixed droplets significantly delayed the nucleation and crystallization of K₂SO₄. This study provides a theoretical basis for extracting potassium sulfate from sulfate-type Salt Lake brine.

Calcitriol, the primary active metabolite of vitamin D, has garnered significant research interest due to its role in several pathologies. However, excessive calcitriol levels or heightened sensitivity of the vitamin D receptor (VDR) can lead to hypercalcemia, motivating the search for analogues that preserve therapeutic activity while reducing adverse effects. Understanding the molecular basis of VDR-calcitriol recognition is therefore essential for rational ligand design. In this study, we applied the ONIOM2(B3LYP/6–31++G(2d,p):PM7) hybrid methodology to characterize VDR-calcitriol interactions and identify the most stable conformations while ensuring computational efficiency. Additionally, TD-DFT calculations were performed to explore its electronic properties. We show that calcitriol remains the dominant chromophore and that its main π → π* transition is subtly influenced by interactions with TRP286 and TYR295, providing residue-level insight that is experimentally inaccessible due to the absence of UV–vis data for the holo complex. Furthermore, the calculated binding energy (−11.88 kcal/mol) is consistent with the experimental affinity of the crystallographic VDR construct, supporting the reliability of the predicted binding mode. This integrated analysis of structural, energetic, and electronic features offers new mechanistic insight into VDR-calcitriol recognition and may guide the development of analogues with improved therapeutic profiles.

This study explores the influence of alkyl chain length and concentration of herbicidal ionic liquids based on (4-chloro-2-methylphenoxy)acetic acid (MCPA) on the structural and mechanical properties of model lipid monolayers composed of phospholipids: 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and sterols (cholesterol, ergosterol). Using the Langmuir monolayer technique, we demonstrate that the effects of [Cn][MCPA] on lipid films strongly depend on both the alkyl chain length and the herbicide concentration. Among the studied compounds, ionic liquids with dodecyl and tetradecyl chains exhibited the most pronounced fluidizing and expanding effects. Dose-dependent experiments revealed that increasing [C12][MCPA] concentrations enhance monolayer expansion and fluidization, with magnitudes varying across lipid types. Penetration experiments simulating dynamic herbicide-membrane interactions indicate a substantial ability of [C12][MCPA] to insert into condensed DMPE and ergosterol monolayers, while insertion into cholesterol and DPPC films is limited. The diverse responses of lipid membranes to [C12][MCPA] suggest the potential to modulate herbicide selectivity toward target and nontarget cell membranes, thereby improving both efficacy and environmental safety. Overall, our findings elucidate key structure–activity relationships governing membrane perturbation by herbicidal ionic liquids and validate Langmuir monolayer studies as an efficient in vitro approach for predicting the biological activity of membrane perturbants. This work provides molecular-level insights that can guide the rational design of selective and safe herbicidal agents.

When nanoparticles and nanoplastics enter biological fluids, their surfaces are rapidly coated with proteins, forming a corona that governs biological responses. However, understanding protein–surface interaction energetics remains a significant challenge. Here, we examine how protein charge distribution affects adsorption to polystyrene nanoparticles (PSNPs) by generating a series of lysine-to-alanine variants of the GB3 protein. This approach is unique because it explores how systematic perturbations in a controlled model protein influence protein–surface interactions. Using isothermal titration calorimetry (ITC), we found that the K19A variant binds most strongly to both nonfunctionalized and carboxylate-functionalized PSNPs. ITC thermograms indicate that K19A forms a stable monolayer, while other variants exhibit multilayer adsorption. The folded protein structure suggests that removing lysine at position 19 creates a flatter, more neutral interaction surface that promotes efficient initial binding. Fluorescence denaturation experiments show that PSNPs destabilize GB3 protein variants, and the binding free energy correlates strongly with protein unfolding (r = 0.82, p < 0.01 for carboxylate-functionalized PSNPs and r = 0.76, p < 0.03 for nonfunctionalized PSNPs). These results reveal how protein stability and charge distribution shape adsorption thermodynamics, informing frameworks for predicting protein–surface interactions.

A tryptophan quadruplex at a protein–protein interface in a dimeric azurin construct mediates 8–11 ns intramolecular as well as interfacial electron hole transfer (HT) triggered by ultrafast photooxidation by a covalently attached organometallic chromophore (Takematsu et al. J. Phys. Chem. B., 2019, 123, 1578–1591). MM/MD and QM/MM/MD simulations characterized intermediates of through-quadruplex HT (i.e., states with one of the tryptophans oxidized) and assessed the feasibility of individual HT pathways. Simulations demonstrated that the oxidized quadruplex in aqueous solution occurs in four distinct states where the charge is predominantly (≥90%) localized at individual tryptophan indoles. Distributions of indole–indole distances, electronic couplings, as well as electrostatic potentials at indoles indicate kinetic and energetic preferences of interfacial over intramolecular ET. Interfacial indoles are tightly solvated by a chain of quasi-structural water molecules that are shielded from bulk water by protein folds. Solvating water molecules support ET by 0.1–0.2 Å shifts toward positively charged indoles. PDB search revealed that 4-Trp clusters are rather common among naturally occurring oxidoreductases.

We present a new class of pseudocyanine iodide (PIC-I) aggregates formed by freeze-induced self-assembly into layered ribbon structures. Unlike conventional PIC J-aggregates with head-to-tail dipole alignment, these ribbons adopt a complex and mixed HJ-aggregate arrangement. Unexpectedly, the aggregate ribbons exhibit intense, red-shifted fluorescence, in contrast to the typical nonemissive nature of their monomer form. At 4 K, their emission lifetimes range from ∼300 ps to ∼1 ns, substantially longer than those of J-aggregates. The combination of red-shifted emission, monomer-like absorption, and extended lifetimes reveals their mixed packing contributions. Second-order autocorrelation measurements with a Hanbury Brown and Twiss interferometer show photon bunching, providing evidence for cooperative emission from collective excitonic states─an effect not previously observed in any aggregates larger than dimers. These findings establish PIC-I HJ-aggregate ribbons as a unique platform for exploring collective photophysics in mixed aggregate molecular assemblies, suggesting potential applications in bioimaging, light-emitting devices, and sensing.

Soluble Aβ oligomers are categorized as major agents of Alzheimer’s disease progression, instead of insoluble fibrils. The binding affinity of Aβ peptides on the gold surface is associated with the biocorona due to the Vroman effect. This phenomenon can be used to screen and/or remove highly toxic amyloid pieces using gold nanoparticles. In this context, the binding process of Aβ₄₀ and Aβ₄₂ dimers to the gold nanosurface was investigated via atomistic simulations, including molecular dynamics (MD) and steered-MD (SMD) simulations. In particular, the obtained results indicate that the Aβ_17–42 dimer exhibits a stronger binding affinity to the gold surface than the Aβ_17–40 dimer in terms of the rupture force, pulling work, and Jarzynski’s free energy analyses. During this process, the van der Waals (vdW) interaction energy plays an important role, and Aβ_17–42 adopts a significantly larger value compared with Aβ_17–40. The enlarged interaction is caused by the additional hydrophobic residues at the C-terminus, including Ile41 and Ala42. Furthermore, free energy landscape outcomes demonstrate that Aβ_17–42 maintains a rigid β-hairpin during the dissociation process, while Aβ_17–40 becomes a random coil.