The Journal of Physical Chemistry B最新文献

Thiocyanate (SCN^-) is known to be a naive ion abundant in biological fluids, blood, and urine. It is also used as a biomarker, as it can penetrate to the brain by crossing the blood brain barrier (BBB) and also gets into the cerebrospinal fluid (CSF) through the blood-CSF barrier. Considering its importance in human physiology, we examine the effect of SCN^- ions on three model proteins: ovalbumin (Ova), bovine serum albumin (BSA), and lysozyme (Lys). We observe that an elevated level of SCN^- (∼0.5 M) leads to an otherwise unusual instant fibrilization of all these proteins at pH 2 at ambient temperature. Field emission scanning electron microscopy (FESEM) and atomic force microscopy (AFM) reveal two distinct initial amyloid-aggregated states: nucleus, protofibril, and two mature fibril states (upon 24 h of incubation): cross-linked network or matrix and bundle-like structures. Despite the structural variation of the three proteins, the formation of these morphologies depends on the counterion: Na⁺ and guanidinium (Gdm⁺). Since these processes are assisted by the associated alteration in protein hydration, we determine individual protein and salt hydration at the thus-obtained different phases using THz-FTIR spectroscopy in the 1.5-22.5 THz (50-750 cm^-1) frequency window. We found that, depending on the counterion, interfacial hydration could act either as a "lubricant" or as a "de-wetting" agent, and the findings can be a potential foundation for future handling of amyloidosis.

In this study, we investigated the stability of the fully activated conformation of the orexin receptor 2 (OX₂R) embedded in a pure POPC bilayer using MD simulations. Various thermodynamic ensembles (i.e., NPT, NVT, NVE, NPAT, μVT, and NPγT) were employed to explore the dynamical heterogeneity of the system in a comprehensive way. In addition, informational similarity metrics (e.g., Jensen-Shannon divergence) as well as Markov state modeling approaches were utilized to elucidate the receptor kinetics. Special attention was paid to assessing surface tension within the simulation box, particularly under NPγT conditions, where 21 nominal surface tension constants were evaluated. Our findings suggest that traditional thermodynamic ensembles such as NPT may not adequately control physical properties of the POPC membrane, impacting the plausibility of the OX₂R model. In general, the performed study underscores the importance of employing the NPγT ensemble for computational investigations of membrane-embedded receptors, as it effectively maintains zero surface tension in the simulated system. These results offer valuable insights for future research aimed at understanding receptor dynamics and designing targeted therapeutics.

Intermolecular spin relaxation by translational diffusion of spin pairs has been widely used to study the properties of biomolecules in liquids. Notably, solvent paramagnetic relaxation enhancement (sPRE) arising from paramagnetic cosolutes has gained significant attention for various applications in structural biology, including the structural refinement of intrinsically disordered proteins, the elucidation of the molecular mechanisms driving cosolute-induced protein denaturation, and the characterization of residue-specific effective near-surface electrostatic potentials (ENS). Furthermore, sPRE has been extensively applied in magnetic resonance imaging (MRI), where paramagnetic ions, such as Gd(III)-based ions, are used as contrast agents. Among these applications, the transverse sPRE rate (Γ₂) has predominantly been interpreted empirically as being proportional to the average interspin distance ⟨r^-6⟩_norm. In this study, we present a rigorous theoretical interpretation of Γ₂ for spherically symmetric intermolecular potentials, demonstrating that it is proportional to ⟨r^-4⟩_norm. We provide an explicit formula for calculating ⟨r^-4⟩_norm without any adjustable parameters, offering valuable insights into the interaction potential independent of the type or strength of interactions. It has broad applicability, including the precise interpretation of the relaxation properties of the MRI contrast agents and calculation of the ENS.

Salts readily alter the physical properties of intrinsically disordered proteins (IDPs) rich in charged residues. Using a coarse-grained IDP model and computer simulations, we investigated how salts affect the heterogeneous conformational ensemble and segment-level structures of the IDP prothymosin-α, classified as a polyelectrolyte. We show that clusters of conformations with distinct structural features are present within the conformational ensemble of prothymosin-α by projecting it onto a two-dimensional latent space with the aid of autoencoders. Although prothymosin-α is inherently disordered, there are preferred transitions between these clusters of conformations. Changing the salt concentration led to the formation of new conformational clusters or/and the disappearance of existing conformational clusters, contributing to changes in IDP properties. Shuffling the Skopelitian domain (C-terminal sequence) of prothymosin-α, known for its anticancer activity, resulted in a different conformational cluster, indicating that clusters with specific structures are related to a particular IDP function. The multiple conformational clusters with distinct structural features could be correlated to different IDP functions, and salts aid or inhibit these functions by modulating the population of conformations in the clusters.

We report a computational protocol for simulating electric field gradient dynamics around Na⁺ cations in mixtures of 1-ethyl-3-methylimidazolium tetrafluoroborate ([Im₂₁][BF₄]) and water validated by comparison to measurements of nuclear magnetic resonance (NMR) T₁ relaxation times. Our protocol combines classical molecular dynamics simulations of a scaled charge model of [Im₂₁][BF₄] and TIP4Pew water to generate the electric field gradient (EFG) correlation function, C_EFG(t), with quantum chemical calculations for determining the EFG variance $⟨V_{zz}^2⟩$. Although we demonstrate that the Sternheimer approximation is as valid in these mixtures as it is in neat water, we do not recommend using the Sternheimer approximation as it underestimates $⟨V_{zz}^2⟩$ by ∼10% compared to a set of computationally efficient density functional theory calculations. Our protocol is capable of reproducing both the composition- and temperature-dependence of T₁ over the full range of experimentally accessible [Im₂₁][BF₄]/water compositions and a temperature range of 285-350 K. We also show that scaling the [Im₂₁][BF₄] charges does not simply speed up the dynamics of the solvent, but has effects on the shape of C_EFG(t). Following validation of our protocol, we analyze the shape and relaxation times of C_EFG(t) to show that the mechanism by with T₁ changes is different when the composition of the mixture varies compared to changes in temperature. As composition changes, the balance between inertial and diffusive relaxation alters, whereas temperature only affects the time scale of the diffusion portion of the relaxation. We also show that solvation shell of Na⁺ in these mixtures is significantly more labile than in neat [Im₂₁][BF₄] and that water and BF₄^- anions compete to be in the Na⁺ solvation shell. This validated computational protocol opens the door to more detailed interpretation of NMR T₁ relaxation experiments of monatomic ions in complex liquid environments.

Crystallization behavior of ibuprofen glass was investigated with focus on the nucleation process and its possible relevance to the cooperatively rearranging region (CRR). The nucleation temperature range of ibuprofen glass was determined by annealing it at various temperatures, followed by observation of the probability of cold crystallization. The temperature to provide the highest probability of nucleation was -15 °C. The effect of the addition of a polymer was also investigated to find that it enhanced and suppressed the crystallization depending on the polymer species and its amount added. The added polymer seemed to influence both nucleation and crystal growth processes by decreasing the glass/nuclei interfacial tension and increasing viscosity, respectively. In addition, the coincidence of the size of CRR in the presence of the polymer with the critical size of nuclei was assumed to enhance nucleation. This finding provides a novel viewpoint for clarifying the nucleation mechanism from supercooled liquids and glasses.

The interaction between amino acids (AAs) and hydration water is fundamental to protein folding and protein-protein interactions. Here, we proposed a hydrophobicity scale for AAs based on their computed free energetic cost of dewetting. This metric captures both entropic and enthalpic contributions of AA-water interactions and allows a systematic and intuitive classification of AAs. Using indirect umbrella sampling (INDUS), we rank individual AAs based on the relative magnitude of their dewetting free energies, from lowest (most hydrophobic) to highest (most hydrophilic). This new hydrophobicity scale is a starting point to evaluate different elements of water hydration behavior, and we focus here on the water structure and translational diffusivity of the hydration waters. While the latter is commonly used as a proxy for hydrophobicity, we show that its behavior is in fact nonmonotonic: hydrophobic residues show slow water diffusion due to highly structured hydration water networks, while highly hydrophilic residues have slow water diffusion due to strong hydrogen bonds with water despite less structured hydration networks. We extend our analysis of hydration properties to intrinsically disordered peptides with varied sequence patterning (sequences of proline/leucine and arginine/glutamic acid residues). We find that the hydration behavior of these peptides is highly context-dependent, with hydrophobic (hydrophilic) patches cooperatively enhancing hydrophobicity (hydrophilicity). These molecular insights of sequence-dependent hydration behaviors may be particularly impactful for the study of intrinsically disordered proteins implicated in liquid-liquid phase separation and aggregation, processes where AAs' hydration environments are complex and changing.

Ferrocene is commonly used as an internal redox couple in electrochemical measurements. Therefore, understanding how the absolute oxidation potential of ferrocene is modulated by different solvents and ion concentrations is important for the comparison of experimental measurements between different electrochemical systems. While standard implicit solvation models may provide relatively good predictions in bulk solvents, they lack the ability to describe ion coordination effects that can substantially alter redox potentials in practical electrolyte systems. In this work, we utilize molecular dynamics simulations to compute absolute oxidation potentials for the ferrocene and decamethylferrocene redox couple in bulk solvents of water, acetonitrile, 1,2-dichloroethane, and trichloromethane, as well as organic electrolytes consisting of mixtures of [BMIM⁺][BF₄^-] ionic liquid and acetonitrile and 1,2-dichloroethane solvents, for a wide range of ion concentrations. The goals are twofold: first, for the bulk solvents, we compare and evaluate the consistency of redox potential predictions for polarizable and nonpolarizable force fields from explicit solvent, free energy simulations, with predictions from an implicit solvent model. Second, we evaluate how ion coordination within the organic electrolytes modulates the redox potential of ferrocene and decamethylferrocene as a function of the ionic concentration and solvent dielectric constant. Utilizing linear response theory, we analyze the solvation contribution to the redox potential in terms of distributions of anion coordination number and how the anion coordination modulates the vertical ionization energy. We show that inclusion of liquid-vacuum interfacial potentials is essential for consistent prediction/interpretation of redox potentials across different solvents and force fields in order to compensate for the artificial quadrupole trace contribution to the solute cavity interfacial potential; this important consideration was previously proposed by Harder and Roux [J. Chem. Phys. 2008, 129, 234706].

Selectivity is a key requirement for membrane-active antimicrobials to be viable in therapeutic contexts. Therefore, the rational design or suitable selection of new compounds requires adequate mechanistic understanding of peptide selectivity. In this study, we compare two similar cyclic peptides that differ only in the arrangement of their three hydrophobic tryptophan (W) and three positively charged arginine (R) residues, yet exhibit different selectivities. This family of peptides has previously been shown to target the cytoplasmic membrane of bacteria, but not to act directly by membrane permeabilization. We have systematically studied and compared the interactions of the two peptides with zwitterionic phosphatidylcholine (PC) and negatively charged phosphatidylglycerol/phosphatidylethanolamine (PG/PE) model membranes using various biophysical methods to elucidate the mechanism of the selectivity. Like many antimicrobial peptides, the cyclic, cationic hexapeptides investigated here bind more efficiently to negatively charged membranes than to zwitterionic ones. Consequently, the two peptides induce vesicle leakage, changes in lipid packing, vesicle aggregation, and vesicle fusion predominantly in binary, negatively charged PG/PE membranes. The peptide with the larger hydrophobic molecular surface (three adjacent W residues) causes all these investigated effects more efficiently. In particular, it induces leakage by asymmetry stress and/or leaky fusion in zwitterionic and charged membranes, which may contribute to high activity but reduces selectivity. The unselective type of leakage appears to be driven by the more pronounced insertion into the lipid layer, facilitated by the larger hydrophobic surface of the peptide. Therefore, avoiding local accumulation of hydrophobic residues might improve the selectivity of future membrane-active compounds.

Two isomeric anions used in Li-ion conducting electrolytes, TFSI and FPFSI, have been compared through quantum-chemical calculations. The FPFSI anion has more low-energy conformers, and its asymmetry leads to an increased number of possible structures of FPFSI-Li complexes. The preferred geometry of the anion-Li ion pair for both anions is the bidentate coordination of the cation through two oxygen atoms; the binding effect is slightly weaker for the FPFSI anion. Ab initio molecular dynamics simulations for salt solutions in tetraglyme have revealed that the amount of cation-to-solvent coordination increases in the LiFPFSI electrolytes. Analysis of the vibrational spectra of anions and ion pairs and the IR spectra of electrolytes obtained from the simulations have indicated that the S-F stretching vibration of the FPFSI anion above 600 cm^-1 can be used in experimental conditions to monitor the FPFSI interactions with lithium cations.