The Journal of Physical Chemistry B最新文献

Cyclic peptides have gained interest as potential therapeutics due to their ability to target specific protein-protein interactions and be membrane-permeable. Understanding the sequence-structure relationship of cyclic peptides would greatly benefit their rational design. However, cyclic peptides tend to adopt multiple conformations in solution, and it remains challenging to use experimental techniques such as solution NMR to delineate their structural ensembles: i.e., the different structures a cyclic peptide adopts and the associated populations. Alternatively, molecular dynamics (MD) simulations can be used to provide such information. However, MD simulations are computationally expensive and not applicable for large-scale screening. Our group has developed the StrEAMM (Structural Ensembles Achieved by Molecular Dynamics and Machine Learning) computational platform and applied it to predict structural ensembles of head-to-tail cyclized pentapeptides and hexapeptides. However, head-to-tail cyclized peptides can be challenging to synthesize due to low yield and complicated reaction workup and product isolation. Furthermore, head-to-tail cyclized peptides are not compatible with screening techniques like mRNA display. Here, we expand the StrEAMM method to thioether-linked cyclic peptides, a popular scaffold in mRNA display. The trained graph neural network models are able to provide fast and simulation-quality structural ensembles for thioether-linked cyclic peptides. Using these models, we identify four thioether-linked cyclic pentapeptides that are predicted to be the best-structured and subsequently experimentally synthesize and characterize them by solution NMR. We observe general agreement between the predicted structures and the NMR results. Ultimately, we envision that StrEAMM-thioether models can work synergistically with the current mRNA platform to streamline the resource-intensive process of drug discovery and design of cyclic peptides.

Aloe vera gel, a polysaccharide-rich, plant-derived hydrogel with excellent biocompatibility and inherent wound-healing activity, was explored as a natural template for iodine delivery as an iodophor in gel form. Although pure aloe vera hydrogel exhibited no significant interaction with iodine, as evident from absorption spectroscopy, it could entrap up to ∼10% available iodine in 3 h. However, more than half of the entrapped iodine was released within the first 2 h, indicating its limited suitability as a standalone iodophor. The entrapment and release characteristics of the aloe vera hydrogel were effectively modulated by blending it with water-soluble polymers such as gelatin or hydroxypropyl cellulose (HPC) to form mixed hydrogel network materials. The iodine entrapment ability increased from 10% by pure aloe vera to 25%, 35%, and 45% upon blending with 20%, 50%, and 80% gelatin, respectively, over ∼6 h time. In contrast, HPC-blended aloe vera hydrogels exhibited slower iodine entrapment of ∼20% over 20 h. Iodine release studies revealed that the rapid release of 50% of the entrapped iodine by pure aloe vera hydrogels in less than 2 h could be significantly reduced to less than 25% over a period of 6 h when blended with 20% gelatin; the release can further be made slower by increasing the amount of gelatin in the mixed hydrogels. Aloe vera-HPC mixed hydrogels, on the other hand, showed a sustained and controlled iodine release steadily increasing to ∼45% over 26 h making it more suitable for long-term antiseptic and wound-healing applications. The mixed hydrogels of aloe vera with gelatin or HPC employed in the present study have been characterized using FTIR, SEM, EDX, and XRD. Raman spectral analysis showed the presence of triiodide (I₃^-) and pentaiodide (I₅^-) as predominant iodine species in the hydrogel matrix.

The microscopic origin of dynamical anomalies in supercooled water remains a long-standing puzzle. Using extensive molecular dynamics simulations and the translational jump-diffusion (TJD) formalism, we reveal that these anomalies originate from rare but crucial translational jumps, which are large-amplitude displacements of water molecules. We discover a distinct structural mechanism for jump initiation, characterized by a coherent sequence of local fluctuations: loss of tetrahedral order, weakening of hydrogen bonds, and a "push-pull solvation" effect marked by the expansion of the first and compression of the second solvation shell. At deeply supercooled temperatures, long-range spatial correlations amplify this collective push-pull effect, leading to a dominant jump contribution to diffusion. Our results establish a direct link between local structural fluctuations and macroscopic transport anomalies, offering a unified microscopic basis for the breakdown of classical transport laws in supercooled water.

³⁵Cl nuclear quadrupole resonance (NQR) and Density functional theory (DFT) computations are combined to characterize chlorine environments in polyvinyl chloride (PVC) and detect structural defects. Calculations validated against reference data enable to classify two main groups of signals: terminal and internal chlorines, the former having ∼1 MHz higher ν. We also predict distinct ³⁵Cl NQR signatures for chlorine vacancies and additional vicinal/geminal chlorines, resulting in an increased ν. Using this methodology, two types of PVC samples are analyzed: commercial high-MW and low-MW PVC. Both show numerous Cl environments associated with both terminal and internal Cl, as well as additional features indicating the presence of Cl defects. Analysis of a partially dechlorinated PVC reveals that dechlorination primarily occurs at the terminal positions, while multichlorinated sites are less reactive and remain mostly untouched. This combined computational-experimental approach demonstrates that ³⁵Cl NQR can sensitively distinguish chlorine sites in PVC, enabling the direct detection of defects relevant to stability, degradation, and recycling strategies.

A new study is presented to elucidate the photodynamics of model carbonyl-substituted polyaromatics targeting the relevance of carbonyl-group orientation and torsional re-equilibration on intersystem crossing (ISC). Our experiments focused on 9-acetylanthracene (9AA) using femtosecond resolved spectroscopy. In the ground state of this molecule, steric interactions force the carbonyl substituent into a near-perpendicular orientation relative to the aromatic system. The time-resolved signals from 9AA show that ISC takes place after spectral shifts that reflect the evolution of the carbonyl group to a slanted geometry as it adjusts to a dihedral angle of around 40° with respect to the aromatic plane. Depending on the solvent, in 9AA manifold crossing takes place on the 3 to 25 ps time-scale. On the other hand, for 2-acetylanthracene (2AA) which is coplanar in both S₀ and S₁, the emission lifetimes can reach several nanoseconds. Analysis of these systems at the highest available theoretical levels reveals further insights into the excited-state dynamics. For 9AA and in contrast with previous publications, it is established that for all relevant geometries, the first excited singlet retains a ππ* character and decays through ISC with no involvement of other singlet states. The manifold crossing involves the interaction with the triplet manifold through states which's transition orbitals are partially localized at the acetyl substituent. Specifically, the slanted geometry of the carbonyl group in 9AA and the potential energy surface around the equilibrium S₁ geometry implies significant spin-orbit interactions and accelerated manifold-crossings. The present results highlight the relevance of substituent reorientation and their slanted geometries which appear to be a dominant feature in carbonyl and nitrated aromatic systems which show rapid ISC dynamics. In the article, we include details on the differences in the mechanisms operating in these two kinds of systems which show the fastest ISC rates among organic chromophores.

Spectroscopic properties of a series of substituted 7-phenylamino-3-(2-pyridyl)coumarins have been characterized, and their ability to form host-guest inclusion complexes with cyclodextrins has been evaluated by the determination of the corresponding host-guest association constants. It has been found that the pyridylcoumarins form 1:1 host-guest complexes with sulfobutylated β-cyclodextrin (Captisol). Their host-guest association constants vary in the range 17-122 dm³ mol^-1, depending on the type of substituent. The association constant decreases with an increase of the electron-withdrawing character of the substituents, which suggests that the pyridylcoumarins interact with positively charged sites within the cyclodextrin cavity. Moreover, the problem associated with the Benesi-Hildebrand method, commonly used for determination of the host-guest association constants, has been clearly demonstrated and the use of an alternative data workup method, based on consecutive iterations methodology, is presented and explained in detail to enable the application of this methodology also to other experimental data sets, not necessarily related to the Benesi-Hildebrand equation.

The higher atomic mass of deuterium basically affects hydrogen-bonding interactions and solvent association, raising critical alarms about the precision of biomolecular measurements executed in heavy water. Herein, we combine linear infrared (IR) spectroscopy, circular dichroism (CD) spectroscopy, molecular dynamics (MD) simulations, and density functional theory (DFT) calculations to explore how solvent isotopic exchange alters protein structure as well as dynamics. Comparative studies of different protonated (H₂O, CH₃OH) and deuterated (D₂O, CD₃OD) solvents expose noticeable differences in hydrogen-bond lifetimes, solvation patterns, and protein secondary structural constancy. Particularly, the amide I hydrogen-bonded complex shows suggestively longer lifetimes in D₂O than in H₂O, reflecting slower hydrogen-bond dynamics and reduced flexibility of the protein backbone. Similar effects are detected in methanol/methanol-d₄, also highlighting that these phenomena are not unique to water but are intrinsic to deuterium replacement. These multitechnique results clearly validate that biomolecular structures and dynamical behaviors in deuterated solvents are markedly different from those in their protonated surroundings. Our conclusions extend the understanding of isotope substitution effects in solvation and underscore the necessity for careful interpretation of experimental data acquired in D₂O or other deuterated solvents, mainly when concluding native biological conditions.

The growing demand for high-energy-density lithium-ion batteries is driving the adoption of high-voltage cathodes and lithium-metal anodes. Recent studies highlight the synergistic role of phosphate and nitrile groups in stabilizing transition-metal cathode interfaces. To leverage this, we employed quantum-chemical calculations and molecular dynamics to design and evaluate a series of cyano-functionalized trimethyl phosphate derivatives as potential electrolyte additives for high-voltage lithium-metal batteries. Multiscale simulations demonstrate that cyano-functionalized trimethyl phosphate derivatives serve as effective interphase modifiers in high-voltage lithium-metal batteries. Introducing cyano groups enhances the oxidation stability while reducing reductive resistance. The electronic effect weakens Li⁺ coordination but strengthens PF₆^- affinity, promoting anion participation in the solvation sheath and facilitating an inorganic-rich interphase formation. Notably, specific molecules form stable seven-membered chelate rings with Li⁺, ensuring their incorporation into the inner solvation structure. Concurrently, most compounds show efficient adsorption toward HF and H₂O, mitigating interfacial corrosion. At the cathode, cyano groups may suppress dissolution under high voltages by chelating transition metals. Building upon these molecular properties, promising high-voltage cathode-stabilizing additives were theoretically screened. Our combined quantum-chemical and molecular-dynamics approach constitutes a broadly applicable framework for the accelerated discovery of an advanced cyano-based electrolyte additive for high-voltage Li-metal batteries.

The main protease (Mpro/3CLpro) of the SARS-CoV-2 virus activates the viral nonstructural proteins (nsp) into functional units inside the host cells and kickstarts the viral replication-translation machinery, acting as a central molecular switch. Each Mpro monomer possesses 12 cysteine residues, none of them participating in disulfide bridge formation in the active state. However, as a form of protection in response to oxidation, Cys145, a component of the Mpro catalytic dyad, may form a disulfide linkage with Cys117 alongside the formation of the NOS/SONOS bridge involving Cys22, Cys44, and Lys61. These redox-induced thiol group modifications, especially the disulfide cross-linking, impart a transient dormancy on the enzyme's catalytic function, which is restored under reducing conditions. In our study, Raman spectroscopy was used to explore the conformational heterogeneity of Mpro cysteines by analyzing the molecular fingerprint of various thiol cross-link rotamers and free cysteine SH bond vibrations. At ambient pH 7.8, distinct disulfide bond vibration signals were observed at ∼510 cm^-1 (GGG) and ∼553 cm^-1 (TGT), alongside an S-H stretch at ∼2564 cm^-1 in the Raman spectra (ex. 532 nm) of the air-oxidized protein sample. Evidence for NOS(nitroso-sulfenamide)/SONOS bridges emerged in the 650-900 cm^-1 region, with the N-O bond stretching vibration mode centered at ∼885 cm^-1. The results validated the presence of both oxidized and reduced conformers of the purified wild-type Mpro in vitro at any given time. Furthermore, the Raman molecular fingerprint of the main protease gives a detailed account of the physical states of various side chain residues and the protein secondary structure and stability by depicting a relatively broad amide 1 band at 1660 cm^-1, having a full width at half maxima (FWHM) of ∼52 cm^-1. Further analysis indicates that about 40% residues are in α-helical (marker band at 1655 cm^-1) conformation space, and β-sheet (component band at ∼1670 cm^-1) preferring residue was about 25% of the total protein content. Raman spectra and intrinsic fluorescence further systematically mapped the specific microenvironment of tryptophan and tyrosine residues and their critical involvement in hydrogen bond formation that significantly contributes to the overall stability and function of the main protease.

Understanding the mechanisms of gas adsorption/desorption and liquid intrusion constitutes a fundamental field that spans physics, chemistry, and engineering and leads to applied problems, such as the characterization of porous materials and porosimetry. The physisorption of gases is typically analyzed at constant temperature for various pressures, and the corresponding isotherms have been classified in standard IUPAC reports, mainly based on empirical considerations. We use classical density functional theory (DFT) to predict the microscopic structure of confined fluids and determine physisorption isotherms for gases, liquids, and supercritical fluids by considering a large range of thermodynamic conditions. The effects of temperature, pore size, and intensity of the fluid-solid interactions are systematically studied. New types of isotherms are identified, and we reinterpret several mechanisms of adsorption and desorption. We propose a new classification of physisorption isotherms organized from a fundamental perspective based on thermodynamic considerations.