The Journal of Physical Chemistry B最新文献

Oxidized derivatives of cholesterol play an important role in the functioning of biomembranes. Unlike other biomolecules, which are physiologically active in only one enantiomeric form, some oxysterols exist endogenously as two stereoisomers that exhibit strictly different biological effects. In this paper, we focused our attention on 22-hydroxycholesterol (22-OH) epimers, 22(R)-OH and 22(S)-OH, and examined their properties in Langmuir monolayers spread at the air/water interface, using classical surface manometry complemented with Brewster angle microscopy (BAM) images of the film texture. The studied epimers showed quite different monolayer characteristics. Namely, 22(S)-OH formed homogeneous, condensed monolayers of high collapse pressure, while 22(R)-OH films were more disordered and expanded with quite low collapse pressure. Interestingly, the latter compound showed in the course of the surface pressure-molecular area isotherm a temperature-dependent plateau transition, characterized by the coexistence of domains of molecules with different inclinations, visible in BAM images as patches of varying brightness. Molecular dynamics (MD) simulations confirmed this and revealed that the greater structural variability of 22(R)-OH is due to the greater hydration of the oxygen atom at C(22) compared to the other epimer. Next, we tested whether 22-OH epimers could differentiate interactions with sphingomyelin (SM). Although the strength of interaction with SM was similar for both epimers, the composition of the films corresponding to this minimum was different. With the aid of MD, it was found that these differences result directly from the interplay between 22-OH molecules and their ability for hydrogen bond formation. Therefore, the stereochemistry of oxysterols seems to play a crucial role in the overall structural organization of the membrane.

Chronic pain is a prevalent problem affecting approximately one out of every five adults in the U.S. The most effective way to treat chronic pain is with opioids, but they cause dangerous side effects such as tolerance, addiction, and respiratory depression, which makes them quite deadly. Opioids, such as fentanyl, target the μ-opioid receptor (MOR), which can then bind to the intracellular G_i protein or the β-arrestin protein. The G_i pathway is primarily responsible for pain relief and potential side effects, but the β-arrestin pathway is chiefly responsible for the unwanted side effects. Ideally, an effective pain medication without side effects would bind to MOR, which would bias signaling solely through the G_i pathway. We used the Bio3D library to conduct principal component analysis to compare the cryo-electron microscopy MOR structure in complex with the G_i versus an X-ray crystallography MOR structure with a nanobody acting as a G_i mimic. Our results agree with a previous study by Munro, which concluded that nanobody-bound MOR is structurally different than G_i-bound MOR. Furthermore, we investigated the structural diversity of opioids that can bind to MOR. Quantum mechanical calculations show that the low energy solution structures of fentanyl differ from the one bound to MOR in the experimental structure, and pK_a calculations reveal that fentanyl is protonated in aqueous solution. Glide docking studies show that higher energy structures of fentanyl in solution form favorable docking complexes with MOR. Our calculations show the relative abundance of each fentanyl conformation in solution as well as the energetic barriers that need to be overcome to bind to MOR. Docking studies confirm that multiple fentanyl conformations can bind to the receptor. Perhaps a variety of conformations of fentanyl can stabilize multiple conformations of the MOR, which can explain why fentanyl can induce different intracellular signaling and multiple physiological effects.

We propose a highly coarse-grained simulation model for crystalline polymer solids with lamellar structures. The mechanical properties of a crystalline polymer solid are mainly determined by the crystalline lamellar structures. This means that coarse-grained models rather than fine-scale molecular models are suitable to study the mechanical properties. We model a crystalline polymer solid by using highly coarse-grained particles, of which the size is comparable to the crystalline layer thickness. One coarse-grained particle consists of multiple subchains and is much larger than monomers. Coarse-grained particles are connected by bonds to form a network structure. Particles are connected by soft but ductile bonds to form a rubber-like network. Particles in the crystalline region are connected by hard but brittle bonds. Brittle bonds are broken when large deformations are applied. We perform uniaxial elongation simulations based on our coarse-grained model. As the applied strain increases, crystalline layers are broken into pieces and nonaffine and collective motions of broken pieces are observed. Our model can successfully reproduce yield behaviors that are similar to typical crystalline polymer solids.

The functional units of natural photosynthetic systems control the process of converting sunlight into chemical energy. In this article, we explore a series of chemically and structurally modified bacteriochlorophyll and chlorophyll pigments through computational chemistry to evaluate their electronic spectroscopy properties. More specifically, we use multiconfigurational and time-dependent density functional theory methods, along with molecular dynamics simulations, to compute the models' energetics both in an implicit and explicit solvent environment. Structural modifications aimed at reducing the planarity of the macrocycle through alkyl-bridge anchoring reveal the significant role of the curvature in fine-tuning spectral properties, which mimics protein scaffold effects on naturally occurring pigments. Furthermore, chemical substitutions with a carbonyl group show potential for expanding absorption spectra toward the blue region, while incorporating an additional double bond decreases absorption efficiency. These insights lay the groundwork to design novel synthetic pigments, with potential applications in artificial light-harvesting systems and more efficient photovoltaic devices.

This study presents a detailed density functional theory (DFT) investigation into the mechanism and energetics of C-H activations catalyzed by bioinspired Fe(IV)O complexes, particularly in the presence of N-hydroxy mediators. The findings show that these mediators significantly enhance the reactivity of the iron-oxo complex. The study examines three substrates with varying bond dissociation energies─ethylbenzene, cyclohexane, and cyclohexadiene─alongside the [Fe(IV)O(N4Py)]²⁺ complex. Mediators N-hydroxyphthalimide (NHPI) and N-hydroxyquinolinimide (NHQI) were chosen for their strong oxidative abilities. The results reveal that NO-H bond cleavage in N-hydroxy compounds occurs more readily than C-H bond cleavage in hydrocarbons, as supported by the Marcus cross-relation applied to H-abstraction. This leads to the rapid formation of aminoxyl radicals, which are more reactive than Fe(IV)O species, lowering the activation energy and enhancing the reaction rate. The C-H bond activation aligns with the Bell-Evans-Polanyi principle, correlating the activation energy with the substrate bond dissociation energy. The investigation reveals that the mediator pathway is favored both thermodynamically and kinetically. Additionally, distortion energy provides a compelling explanation for the observed reactivity trends, further highlighting NHQI's superior efficiency compared to NHPI. Additionally, quantum mechanical tunneling plays a significant role, as evidenced by the computed kinetic isotope effect, which matches experimental data.

Dexter energy transfer (DET) of triplet electronic states is used to direct energy in photovoltaics, quench reactive singlet oxygen species in biological systems, and generate them in photodynamic therapy. However, the extent to which repeated DET between aromatic residues can lead to triplet energy migration in proteins has not been investigated. Here, we computationally describe DET rates in microtubules, actin filaments and the intermediate filament, vimentin. We discover instances where interaromatic residue Dexter couplings within individual protein subunits of these polymers are similar those of small molecules used for organic electronics. However, interaromatic residue coupling is mostly weak (<10^-3 eV), limiting triplet energy diffusion lengths to 6.1, 0.5 and 1.0 Å in microtubules, actin filaments and vimentin, respectively. On the other hand, repeated förster resonance energy transfer (FRET) between aromatic residues leads to singlet energy diffusion lengths of 12.4 Å for actin filaments and about 8.6 Å for both microtubules and vimentin filaments. Our work shows that singlet energy migration dominates over triplet energy migration in cytoskeletal polymers.

Hydrogen-deuterium exchange (HDX) measured by small-angle neutron scattering (HDX-SANS) is used to measure HDX in bovine serum albumin (BSA) under different temperatures and formulation conditions. HDX-SANS measurements are performed at 40, 50, and 60 °C in D₂O after storing proteins at 4 °C for 1 week to pre-exchange the readily accessible hydrogens. This enables us to probe the long-time HDX of protons at the core of the BSA proteins, which is more challenging for solvent molecules to access. The HDX kinetics are observed to follow an Arrhenius behavior with an apparent activation energy of 81.4 ± 1 kJ/mol, which is composed of the energy for protein conformational fluctuations and that for exchanging an amide hydrogen. Adding a tonicity agent of 150 mM NaCl has only a very slight effect on the HDX kinetics. Interestingly, we also observed that the formulation with faster HDX kinetics has a lower onset temperature of denaturation. This observation is qualitatively consistent with a previous study of HDX-SANS on a monoclonal antibody (mAb), despite the large difference of the secondary structure between BSA, dominated by alpha helices, and mAb, which is predominantly composed of β-sheets.

Understanding crystallization behavior is integral to the design of pharmaceutical compounds for which the pharmacological properties depend on the crystal forms achieved. Very often, these crystals are based on hydrophobic molecules. One method for delivering crystal-forming hydrophobic drugs is by means of lipid nanoparticle carriers. However, so far, a characterization of the potential crystallization of fully hydrophobic molecules in a lipid environment has never been reported. In this work we investigate the crystallization behavior of two model hydrophobic chains, n-eicosane (C20) and n-triacontane (C30), in phospholipid bilayers. We combine static ²H nuclear magnetic resonance (NMR) spectroscopy and differential scanning calorimetry (DSC) and show that C30 molecules can indeed crystallize inside DMPC and POPC bilayers. The phase transition temperatures of C30 are slightly reduced inside DMPC, and rotator phase formation becomes a two-step process: Preorganized n-alkane chains assemble in rotator-phase crystallites just as fast as bulk C30, but further addition of molecules is notably slower. Under the same isothermal conditions, different crystal forms can be obtained by crystallization in the membrane and in bulk. In excess water conditions, homogeneous nucleation of C30 is observed. The initial anisotropic molecular arrangement of C30 molecules in the membrane is readily recovered upon reheating, showing reversibility. The shorter C20 molecules on the other hand become trapped in the DMPC membrane gel-phase upon cooling and do not crystallize. This work marks the first observation of the crystallization of hydrophobic chains inside a lipid bilayer environment. As such, it defines a fundamental starting point for studying the crystallization characteristics of various hydrophobic molecules in lipid membranes.

Multidrug resistance (MDR) to conventional antibiotics is one of the most urgent global health threats, necessitating the development of effective and biocompatible antimicrobial agents that are less inclined to provoke resistance. Structurally nanoengineered antimicrobial peptide polymers (SNAPPs) are a novel and promising class of such alternatives. These star-shaped polymers are made of a dendritic core with multiple arms made of copeptides with varying amino acid sequences. Through a comprehensive set of in vivo experiments, we previously showed that SNAPPs with arms made of random blocks of lysine (K) and valine (V) residues exhibit sub-μM efficacy against Gram-negative and Gram-positive bacteria tested. Cryo-TEM images suggested pore formation by a SNAPP with random block copeptide arms as one of their modes of actions. However, the molecular mechanisms responsible for this mode of action of SNAPPs are not fully understood. To address this gap, we employed an atomistic molecular dynamics simulation technique to investigate the influence of three different sequences of amino acids, namely (1) alt-block KKV, (2) ran-block, and (3) diblock motifs on the secondary structure of their arms and SNAPP's overall configuration as well as their interactions with lipid bilayer. We, for the first time, identified a step-by-step mechanism through which alt-block and random SNAPPs interact with lipid bilayer and lead to "pore formation", hence, cell death. These insights provide a strong foundation for further optimization of the chemical structure of SNAPPs for maximum performance against MDR bacteria, therefore offering a promising avenue for addressing antibiotic resistance and the development of effective antibacterial agents.

We developed a systematic polarizable force field for molten trivalent rare-earth chlorides, from lanthanum to europium, based on first-principle calculations. The proposed model was employed to investigate the local structure and physicochemical properties of pure molten salts and their mixtures with sodium chloride. We computed densities, heat capacities, surface tensions, viscosities, and diffusion coefficients and disclosed their evolution along the lanthanide series, filling the gaps for poorly studied elements, such as promethium and europium. The analysis of the local arrangement of chloride anions around lanthanide cations revealed broad coordination number distributions with a typical [from 6 to 9]-fold environment, the maximum of which shifts toward lower values with the increase of atomic number as well as upon dilution of the salt in sodium chloride. The neighboring lanthanide chloride complexes were found to be connected by sharing a corner or an edge of the corresponding polyhedra.