The 50 most-cited articles in The Journal of Physical Chemistry B, 2022

Deep eutectic solvents (DESs) formed by hydrogen bond donors and acceptors are a promising new class of solvents. Both hydrophilic and hydrophobic binary DESs readily absorb water, making them ternary mixtures, and a small water content is always inevitable under ambient conditions. We present a thorough study of a typical hydrophobic DES formed by a 1:2 mole ratio of tetrabutyl ammonium chloride and decanoic acid, focusing on the effects of a low water content caused by absorbed water vapor, using multinuclear NMR techniques, molecular modeling, and several other physicochemical techniques. Already very low water contents cause dynamic nanoscale phase segregation, reduce solvent viscosity and fragility, increase self-diffusion coefficients and conductivity, and enhance local dynamics. Water interferes with the hydrogen-bonding network between the chloride ions and carboxylic acid groups by solvating them, which enhances carboxylic acid self-correlation and ion pair formation between tetrabutyl ammonium and chloride. Simulations show that the component molar ratio can be varied,…

AlphaFold has burst into our lives. A powerful algorithm that underscores the strength of biological sequence data and artificial intelligence (AI). AlphaFold has appended projects and research directions. The database it has been creating promises an untold number of applications with vast potential impacts that are still difficult to surmise. AI approaches can revolutionize personalized treatments and usher in better-informed clinical trials. They promise to make giant leaps toward reshaping and revamping drug discovery strategies, selecting and prioritizing combinations of drug targets. Here, we briefly overview AI in structural biology, including in molecular dynamics simulations and prediction of microbiota-human protein-protein interactions. We highlight the advancements accomplished by the deep-learning-powered AlphaFold in protein structure prediction and their powerful impact on the life sciences. At the same time, AlphaFold does not resolve the decades-long protein folding challenge, nor does it identify the folding pathways. The models that AlphaFold provides do not…

High Resolution Image Download MS PowerPoint Slide Elucidating the state of interfacial water, especially the hydrogen-bond configurations, is considered to be key for a better understanding of the functions of polymers that are exhibited in the presence of water. Here, an analysis in this direction is conducted for two water-insoluble biocompatible polymers, poly(2-methoxyethyl acrylate) and cyclic(poly(2-methoxyethyl acrylate)), and a non-biocompatible polymer, poly( n -butyl acrylate), by measuring their IR spectra under humidified conditions and by carrying out theoretical calculations on model complex systems. It is found that the OH stretching bands of water are decomposed into four components, and while the higher-frequency components (with peaks at ∼3610 and ∼3540 cm –1 ) behave in parallel with the C═O and C–O–C stretching and CH deformation bands of the polymers, the lower-frequency components (with peaks at ∼3430 and ∼3260 cm –1 ) become pronounced to a greater extent with increasing humidity. From the theoretical calculations, it is shown that the OH stretching frequency…

High Resolution Image Download MS PowerPoint Slide Identifying the p K a values of aspartic acid (Asp) and glutamic acid (Glu) in active sites is essential for understanding enzyme reaction mechanisms. In this study, we investigated the correlation between the C═O stretching vibrational frequency (ν C═O ) of protonated carboxylic acids and the p K a values using density functional theory calculations. In unsaturated carboxylic acids (e.g., benzoic acid analogues), ν C═O decreases as the p K a increases (the negative correlation), whereas in saturated carboxylic acids (e.g., acetic acid analogues, Asp, and Glu), ν C═O increases as the p K a increases (the positive correlation) as long as the structure of the H-bond network around the acid is identical. The negative/positive correlation between ν C═O and p K a can be rationalized by the presence or absence of the C═C double bond. The p K a shift was estimated from the ν C═O shift of Asp and Glu in proteins on the basis of the negative correlation derived from benzoic acids. The previous estimations should be revisited by using the…

Midinfrared photothermal (MIP) microscopy, also called optical photothermal infrared (O-PTIR) microscopy, is an emerging tool for bond-selective chemical imaging of living biological and material samples. In MIP microscopy, a visible probe beam detects the photothermal-based contrast induced by a vibrational absorption. With submicron spatial resolution, high spectral fidelity, and reduced water absorption background, MIP microscopy has overcome the limitations in infrared chemical imaging methods. In this review, we summarize the basic principle of MIP microscopy, the different origins of MIP contrasts, and recent technology development that pushed the resolution, speed, and sensitivity of MIP imaging to a new stage. We further emphasize its broad applications in life science and material characterization, and provide a perspective of future technical advances.

Deep eutectic solvents have quickly attracted the attention of researchers because they better meet the requirements of green chemistry and thus have the potential to replace conventional hazardous organic solvents in some areas. To better understand the nature of these mixtures, as well as expand the possibilities of their use in different industries, a detailed examination of their physical properties, such as density, viscosity, the nature of the interactions between their constituents, the phase diagrams, depression of their melting point, and interpretation of these results is necessary. In this work, the mixtures of tetrabutylammonium bromide (TBAB) and nonanoic acid (NA) in different molar ratios are theoretically and experimentally investigated by applying a phase diagram constructed on the basis of differential scanning calorimetry measurements and COSMO-RS model. Spectral properties are investigated based on Fourier transform infrared spectroscopy and density functional theory. The observed eutectic point indicates the formation of a DES in the TBAB-NA system in a 1:2…

Liquid electrolytes are the most common electrolyte classes used in Li-ion batteries, which are a critical technology of the modern world. However, we still lack the computational tools required to accurately calculate key properties of these materials (viscosity, ionic diffusivity) from first principles necessary to sup-port improved designs. In this work, we report a machine learning-based force field for liquid electrolyte simulations which bridges the gap between the accuracy of range-separated hybrid density functional theory and the efficiency of classical force fields. Predictions of material properties made with this force field are quantitatively accurate compared to experimental data. Our model uses the QRNN deep neural network architecture, which includes both long-range interactions and global charge equilibration. The training dataset is composed solely of non-periodic DFT, allowing the practical use of an accurate theory (here, ωB97X-D3BJ/def2-TZVPD) which would be prohibitively expensive for generating large datasets with periodic DFT. In this report we focus on seven…

Bacterial ice nucleators (INs) are among the most effective ice nucleators known and are relevant for freezing processes in agriculture, the atmosphere, and the biosphere. Their ability to facilitate ice formation is due to specialized ice-nucleating proteins (INPs) anchored to the outer bacterial cell membrane, enabling the crystallization of water at temperatures up to -2 °C. In this Perspective, we highlight the importance of functional aggregation of INPs for the exceptionally high ice nucleation activity of bacterial ice nucleators. We emphasize that the bacterial cell membrane, as well as environmental conditions, is crucial for a precise functional INP aggregation. Interdisciplinary approaches combining high-throughput droplet freezing assays with advanced physicochemical tools and protein biochemistry are needed to link changes in protein structure or protein-water interactions with changes on the functional level.

. Extensive testing of DES-Amber indicates that it can describe the thermal stability and conformational flexibility of single- and double-stranded DNA systems with a level of accuracy comparable to or, especially for disordered systems, exceeding that of state-of-the-art nucleic acid force fields. Finally, we show that, in certain favorable cases, DES-Amber can be used for long-timescale simulations of protein-nucleic acid complexes.

In this paper, the solubility of methane in water along the 400 bar isobar is determined by computer simulations using the TIP4P/Ice force field for water and a simple LJ model for methane.In particular, the solubility of methane in water when in contact with the gas phase and the solubility of methane in water when in contact with the hydrate has been determined.The solubility of methane in a gas-liquid system decreases as temperature increases.The solubility of methane in a hydrateliquid system increases with temperature.The two curves intersect at a certain temperature that determines the triple point T 3 at a certain pressure.We also determined T 3 by the three-phase direct coexistence method.The results of both methods agree, and we suggest 295(2) K as the value of T 3 for this system.We also analyzed the impact of curvature on the solubility of methane in water.We found that the presence of curvature increases the solubility in both the gas-liquid and hydrate-liquid systems.The change in chemical potential for the formation of hydrate is evaluated along the isobar using two…

self-diffusivities and solubilities in NaOH and KOH solutions, which can be used for process design and optimization of efficient alkaline electrolyzers and fuel cells.

There is a long, ongoing debate on how small molecules (osmolytes) affect the stability of proteins. The present study found that change in collective rotational dynamics of water in osmolyte solutions likely has a dominant effect on protein denaturation. According to THz spectroscopy analysis, osmolytes that stabilize proteins are accompanied by bound hydration water with slow dynamics, while the collective rotational dynamics of water is accelerated in the case of denaturant osmolytes. Among 15 osmolytes studied here, there is a good correlation between the change in mobility in terms of water rotational dynamics and the denaturation temperature of ribonuclease A. The changes in water dynamics due to osmolytes can be regarded as a pseudo-temperature-change, which agrees well with the change in protein denaturation temperature. These results indicate that the molecular dynamics of water around the protein is a key factor for protein denaturation.

Carbon dots (CDs) are one of the most versatile nanomaterials discovered in the 21st century. They possess many properties and thus hold potentials in diverse applications. While an increasing amount of attention has been given to these novel nanoparticles, the broad scientific community is actively engaged in exploring their limits. Recent studies on the fractionalization and assembly of CDs further push the limits beyond just CDs and demonstrate that CDs are both a mixture of heterogeneous fractions and promising building blocks for assembly of large carbon-based materials. With CDs moving forward toward both microscopic and macroscopic levels, a good understanding of the structure-property-activity relationships is essential to forecasting the future of CDs. Hence, in this Perspective, structure-property-activity relationships are highlighted based on the repeatedly verified findings in CDs. In addition, studies on CD fractionalization and assembly are briefly summarized in this Perspective. Eventually, these structure-property-activity relationships and controllability are…

Adsorption of small amphiphilic molecules occurs in various biological and technological processes, sometimes desired while other times unwanted (e.g., contamination). Surface-active molecules preferentially bind to interfaces and affect their wetting properties. We use molecular dynamics simulations to study the adsorption of short-chained alcohols (simple surfactants) to the water-vapor interface and solid surfaces of various polarities. With a theoretical analysis, we derive an equation for the adsorption coefficient, which scales exponentially with the molecular surface area and the surface wetting coefficient and is in good agreement with the simulation results. We apply the outcomes to aqueous sessile droplets containing surfactants, where the competition of surfactant adsorptions to both interfaces alters the contact angle in a nontrivial way. The influence of surfactants is the strongest on very hydrophilic and hydrophobic surfaces, whereas droplets on moderately hydrophilic surfaces are less affected.

Some molecules of chemical and biological significance possess vibrations with significant Herzberg-Teller (HT) couplings, which render the Franck-Condon (FC) approximation inadequate and cause the breakdown of the well-known mirror-image symmetry between linear absorption and emission spectra. Using a model two-state system with displaced harmonic potential surfaces, we show analytically that the FC-HT interference gives rise to asymmetric intensity modification, which has the same sign for all transitions on one side of the 0-0 absorption line and the opposite sign in the equivalent fluorescence transitions, while the trend is exactly reversed for all transitions on the other side the 0-0 line. We examine the dependence of the absorption-emission asymmetry on the mode frequency, Huang-Rhys factor, and dipole moment parameters to show the recovery of symmetry with particular combinations of parameters and a crossover from fluorescence to absorption dominance. We illustrate the analytical predictions through numerically exact calculations in models of one and two discrete…

The phospholipid lecithin (L) and the nonionic surfactant Tween 80 (T) are used together in various contexts, including in drug delivery and oil spill remediation. There is hence a need to elucidate the nanostructures in LT mixtures, which is the focus of this paper. We study these mixtures using cryogenic transmission electron microscopy (cryo-TEM), coupled with dynamic light scattering and small-angle neutron scattering. As the concentration of Tween 80 is increased, the vesicles formed by lecithin are transformed into spherical micelles. We identify bicelles (i.e., disc-like micelles) as well as cylindrical micelles as the key stable nanostructures formed at intermediate L/T ratios. The bicelles have diameters ∼13-26 nm, and the bicelle size decreases as the Tween 80 content increases. We propose that the lecithin lipids form the body of the discs, while the Tween 80 surfactants occupy the rims. This hypothesis is consistent with geometric arguments because lecithin is double-tailed and favors minimal curvature, whereas the single-tailed Tween 80 molecules prefer curved…

Diminishing fossil fuel-based resources and ever-growing environmental concerns related to plastic pollution demand for the development of sustainable and biodegradable polymeric material alternatives. Polyhydroxyalkanoates (PHAs) represent an eco-friendly and economically viable class of polymers with a wide range of applications. However, the chemical diversity combined with tunable physical properties available within PHAs poses discovery and optimization challenges with respect to identifying optimal application-specific chemical compositions. Here we use an example of melting temperature ( T m ) prediction to demonstrate the promise of machine learning (ML)-based techniques for establishing efficient structure–property mappings in PHA-based chemical space. We employ a manually curated data set of experimentally measured T m values for a wide range of PHA homo- and copolymer chemistries along with their reported polymer molecular weights and polydispersity indices. Descriptors based on topology, shape, and charge/polarity of specific motifs forming the polymer backbone were then…

The diffusion of poly(ethylene glycol) methyl ether thiol (PEGSH)-functionalized gold nanoparticles (NPs) was measured in polyacrylamide gels with various cross-linking densities. The molecular weight of the PEGSH ligand and particle core size were both varied to yield particles with hydrodynamic diameters ranging from 7 to 21 nm. The gel mesh size was varied from approximately 36 to 60 nm by controlling the cross-linking density of the gel. Because high-molecular-weight ligands are expected to yield more compressible particles, we expected the diffusion constants of the NPs to depend on their hard/soft ratios (where the hard component of the particle consists of the particle core and the soft component of the particle consists of the ligand shell). However, our measurements revealed that NP diffusion coefficients resulted primarily from changes in the overall hydrodynamic diameter and not the ratio of particle core size to ligand size. Across all particles and gels, we found that the diffusion coefficient was well predicted by the confinement ratio calculated from the diameter of…

Studying chemical processes at the air–water interface is always challenging. A recent report claimed that H 2 O 2 was formed spontaneously on the surface of condensed water microdroplets. However, a newer report concluded that the detected H 2 O 2 in the previous report could originate in part from the water vapor source that involved ultrasonic atomization of liquid water. Here, this phenomenon is reinvestigated regarding the influence of ultrasonic cavitation, surface modification of droplets, and solutes in the bulk liquid on H 2 O 2 production. When the droplet surfaces were modified by surfactants, H 2 O 2 production did not change, whereas adding gases or inorganic compounds to the bulk solution caused significant changes in H 2 O 2 production. These results confirm that H 2 O 2 formation originates from cavitation in bulk solutions. It is concluded that the air–water interface of water microdroplets itself does not generate H 2 O 2 .

Ionic liquids (ILs) are charged fluids composed of anions and cations of different size and shape. The ordering of charge and density in ILs confined between charged interfaces underlies numerous applications of IL electrolytes. Here, we analyze the screening behavior and the resulting structural forces of a representative IL confined between two charge-varied plates. Using both molecular dynamics simulations and a continuum theory, we contrast the screening features of a more-realistic asymmetric system and a less-realistic symmetric one. The ionic size asymmetry plays a nontrivial role in charge screening, affecting both the ionic density profiles and the disjoining pressure distance dependence. Ionic systems with size asymmetry are stronger coupled systems, and this manifests itself both in their response to the electrode polarization and spontaneous structure formation at the interface. Analytical expressions for decay lengths of the disjoining pressure are obtained in agreement with the pressure profiles computed from molecular dynamics simulations.

A theory for sequence-dependent liquid-liquid phase separation (LLPS) of intrinsically disordered proteins (IDPs) in the study of biomolecular condensates is formulated by extending the random phase approximation (RPA) and field-theoretic simulation (FTS) of heteropolymers with spatially long-range Coulomb interactions to include the fundamental effects of short-range, hydrophobic-like interactions between amino acid residues. To this end, short-range effects are modeled by Yukawa interactions between multiple nonelectrostatic charges derived from an eigenvalue decomposition of pairwise residue-residue contact energies. Chain excluded volume is afforded by incompressibility constraints. A mean-field approximation leads to an effective Flory-Huggins χ parameter, which, in conjunction with RPA, accounts for the contact-interaction effects of amino acid composition and the sequence-pattern effects of long-range electrostatics in IDP LLPS, whereas FTS based on the formulation provides full sequence dependence for both short- and long-range interactions. This general approach is…

-dimethylacrylamide-water systems were performed. The results show that the mean diffusion coefficient of water drastically decreases in the middle dehydration stage. In this stage, the mobilities of water are restrained because part of the water forms hydrogen bonds to bind polymer chains due to a glass transition. In addition to the three well-known types of water (i.e., bound, intermediate, and free water) around hydrophilic polymers in hydrogels, our results suggest that the intermediate water can be further classified into two types: first and second intermediate water. The bound and first intermediate water acts as a cross-linker between polymer chains, even if the polymer does not form intra- or intermolecular bonds itself. The diffusive properties of water might have important implications for the interpretation of properties of polymer hydrogels.

The electrolyte ion diffusion kinetics have an important impact on electrochemical energy storage. Herein, we report the effect of the intrinsic porosity of NiCoP on accelerating electrolyte ion diffusion kinetics and accommodating volume expansion during the charge/discharge process. The pore distribution model of electrode/electrolyte was designed and optimized by the finite element simulation, demonstrating the visualization and quantitative analysis of the diffusion process of the electrode/electrolyte interface with intrinsic porous structure. When the pore area ratio reached 50.01%, the theoretical diffusion coefficient of 1.41 × 10 –11 m 2 s –1 would be conducive to the rapid diffusion of electrolytes. The electrode gained a specific capacity of 2805 F g –1 at a current density of 1 A g –1 based on the measured diffusion coefficient (1.79 × 10 –10 m 2 s –1 ), superior to 1.44-times that of the pristine electrode. The diffusion barriers of intrinsic porous NiCoP (3.19 eV) and conventional NiCoP (47.10 eV) were calculated by the density functional theory calculations,…

The substrate roughness is a very important parameter that can influence the properties of supported thin films. In this work, we investigate the effect of surface roughness on the properties of a vapor-deposited glass (celecoxib, CXB) both in its bulk and in confined states. Using dielectric spectroscopy, we provide experimental evidence depicting a profound influence of surface roughness on the α-relaxation dynamics and the isothermal crystallization of this vapor-deposited glass. Besides, we have verified the influence of film confinement on varying values of surface roughnesses as well. At a fixed surface roughness value, the confinement could alter both the dynamics and crystallization of vapor-deposited CXB.

In this study, we examine the spectral dielectric properties of liquid water in charged nanopores over a wide range of frequencies (0.3 GHz to 30 THz) and pore widths (0.3 to 5 nm). This has been achieved using classical molecular dynamics simulations of hydrated Na-smectite, the prototypical swelling clay mineral. We observe a drastic (20-fold) and anisotropic decrease in the static relative permittivity of the system as the pore width decreases. This large decrement in static permittivity reflects a strong attenuation of the main Debye relaxation mode of liquid water. Remarkably, this strong attenuation entails very little change in the time scale of the collective relaxation. Our results indicate that water confined in charged nanopores is a distinct solvent with a much weaker collective nature than bulk liquid water, in agreement with recent observations of water in uncharged nanopores. Finally, we observe remarkable agreement between the dielectric properties of the simulated clay system against a compiled set of soil samples at various volumetric water contents. This implies…

The approximately linear scaling of fluorescence quantum yield (ϕ) with fluorescence lifetime (τ) in fluorescent proteins (FPs) has inspired engineering of brighter fluorophores based on screening for increased lifetimes. Several recently developed FPs such as mTurquoise2, mScarlet, and FusionRed-MQV which have become useful for live cell imaging are products of lifetime selection strategies. However, the underlying photophysical basis of the improved brightness has not been scrutinized. In this study, we focused on understanding the outcome of lifetime-based directed evolution of mCherry, which is a popular red-FP (RFP). We identified four positions (W143, I161, Q163, and I197) near the FP chromophore that can be mutated to create mCherry-XL (eXtended Lifetime: ϕ = 0.70; τ = 3.9 ns). The 3-fold higher quantum yield of mCherry-XL is on par with that of the brightest RFP to date, mScarlet. We examined selected variants within the evolution trajectory and found a near-linear scaling of lifetime with quantum yield and consistent blue-shifts of the absorption and emission spectra. We…

Flavins are highly versatile redox-active and colored cofactors in a large variety of proteins. These do include photoenzymes and photoreceptors, although the vast majority performs non-light-driven physiological functions. Nevertheless, electron transfer between flavins and specific nearby amino acid residues (in particular tyrosine, tryptophan, and presumably histidine and arginine) takes place upon excitation of flavin in many flavoproteins. For oxidized flavoproteins these reactions potentially have a photoprotective role. In this Perspective, we outline work on the characterization of early reaction intermediates not only in the relatively well-studied resting oxidized forms but also in the fully reduced and the intrinsically unstable semireduced forms, where ultrafast photooxidation of flavin was recently demonstrated. Along different lines, flavoprotein-based novel photocatalysts for biotechnological applications are presently emerging, employing both substrate photooxidation and photoreduction strategies. Deep insight into the fundamental flavin photochemical reactions may…

The emergence of the variant of concern Omicron (B.1.1.529) of the severe acute respiratory syndrome coronavirus 2 has aggravated the Covid-19 pandemic due to its very contagious ability. The high infection rate may be due to the high binding affinity of Omicron to human cells, but both experimental and computational studies have yielded conflicting results on this issue. Some studies have shown that the Omicron variant binds to human angiotensin-converting enzyme 2 (hACE2) more strongly than the wild type (WT), but other studies have reported comparable binding affinities. To shed light on this open problem, in this work, we calculated the binding free energy of the receptor binding domain (RBD) of the WT and Omicron spike protein to hACE2 using all-atom molecular dynamics simulation and the molecular mechanics Poisson-Boltzmann surface area method. We showed that Omicron binds to human cells more strongly than the WT due to increased RBD charge, which enhances electrostatic interaction with negatively charged hACE2. N440K, T478K, E484A, Q493R, and Q498R mutations in the RBD have…

Epoxy resins are widely used as matrix resins, especially for carbon-fiber-reinforced plastic, due to their outstanding physical and mechanical properties. To date, most research into cross-linking processes using simulation has considered only a distance-based criterion to judge the probability of reaction. In this work, a new algorithm was developed for use with the large-scale atomic/molecular massively parallel simulator (LAMMPS) simulation package to study the cross-linking process; this new approach combines both a distance-based criterion and several kinetic criteria to identify whether the reaction has occurred. Using this simulation framework, we investigated the effect of model size on predicted thermomechanical properties of three different structural systems: diglycidyl ether of bisphenol A (DGEBA)/4,4'-diaminodiphenyl sulfone (4,4'-DDS), DGEBA/diethylenetriamine (DETA), and tetraglycidyl diaminodiphenylmethane (TGDDM)/4,4'-DDS. Derived values of gel point, volume shrinkage, and cross-linked resin density were found to be insensitive to model size in these three systems.…

Flavonols have been studied extensively because of their interesting biological activities and excited-state intramolecular proton transfer (ESIPT) behavior. Galangin, kaempferol, quercetin, and myricetin are structurally related flavonols that differ only in the number of B-ring hydroxyl substituents. In this work, we have carried out a detailed study on the photophysical behavior of these structurally related flavonols in various solvents and a 1,2-dimyristoyl- sn -glycero-3-phosphocholine (DMPC) small unilamellar vesicles (SUVs) model membrane. We observed that these flavonols exist in different forms in the ground and excited states depending on the nature of the solvent. The weak intrinsic fluorescence of these flavonols gets enhanced in hydrogen-bond-accepting and alcoholic solvents. The phototautomer fluorescence intensity of these flavonols increases significantly in the DMPC membrane compared to water, suggesting ESIPT activation via binding interaction between flavonols and the membrane. According to our findings, both the number of B-ring hydroxy groups and membrane…

Lipid droplets (LDs) are intracellular organelles whose primary function is energy storage. Known to emerge from the endoplasmic reticulum (ER) bilayer, LDs have a unique structure with a core consisting of neutral lipids, triacylglycerol (TG) or sterol esters (SE), surrounded by a phospholipid (PL) monolayer and decorated by proteins that come and go throughout their complex lifecycle. In this Feature Article, we review recent developments in computational studies of LDs, a rapidly growing area of research. We highlight how molecular dynamics (MD) simulations have provided valuable molecular-level insight into LD targeting and LD biogenesis. Additionally, we review the physical properties of TG from different force fields compared with experimental data. Possible future directions and challenges are discussed.

-methylglycine─NMG) by means of infrared spectroscopy. GLY and NMG were clearly limited as minimal models for unfolded proteins and should be treated with caution. We isolated the spectral share of water changed simultaneously by the biomacromolecule/model molecule and the osmolyte, which allowed us to provide unambiguous experimental arguments for the mechanism of stabilization/destabilization of proteins by osmolytes. In the case of both types of osmolytes, the decisive factor determining the equilibrium folded/unfolded state of protein was the enthalpy effect exerted on the hydration spheres of proteins in both forms. In the case of stabilizing osmolytes, enthalpy was also favored by entropy, as the unfolded state of a protein was more entropically destabilized than the folded state.

The hydration structure of Na+ and K+ ions in solution is systematically investigated using a hierarchy of molecular models that progressively include more accurate representations of many-body interactions. We found that a conventional empirical pairwise additive force field that is commonly used in biomolecular simulations is unable to reproduce the extended X-ray absorption fine structure (EXAFS) spectra for both ions. In contrast, progressive inclusion of many-body effects rigorously derived from the many-body expansion of the energy allows the MB-nrg potential energy functions (PEFs) to achieve nearly quantitative agreement with the experimental EXAFS spectra, thus enabling the development of a molecular-level picture of the hydration structure of both Na+ and K+ in solution. Since the MB-nrg PEFs have already been shown to accurately describe isomeric equilibria and vibrational spectra of small ion–water clusters in the gas phase, the present study demonstrates that the MB-nrg PEFs effectively represent the long-sought-after models able to correctly predict the properties of…

We report the effects of quercetin, a flavonoid present in the human diet, on early stage beta-amyloid (Aβ) aggregation, a seminal event in Alzheimer's disease. Molecular level changes in Aβ arrangements are monitored by time-resolved emission spectral (TRES) measurements of the fluorescence of Aβ's single tyrosine intrinsic fluorophore (Tyr). The results suggest that quercetin binds β-amyloid oligomers at early stages of their aggregation, which leads to the formation of modified oligomers and hinders the creation of β-sheet structures, potentially preventing the onset of Alzheimer's disease.

Substrate inhibition, whereby enzymatic activity decreases with excess substrate after reaching a maximum turnover rate, is among the most elusive phenomena in enzymatic catalysis. Here, based on a dynamic energy landscape model, we investigate the underlying mechanism by performing molecular simulations and frustration analysis for a model enzyme adenylate kinase (AdK), which catalyzes the phosphoryl transfer reaction ATP + AMP ⇋ ADP + ADP. Intriguingly, these reveal a kinetic repartitioning mechanism of substrate inhibition, whereby excess substrate AMP suppresses the population of an energetically frustrated, but kinetically activated, catalytic pathway going through a substrate (ATP)-product (ADP) cobound complex with steric incompatibility. Such a frustrated pathway plays a crucial role in facilitating the bottleneck product ADP release, and its suppression by excess substrate AMP leads to a slow down of product release and overall turnover. The simulation results directly demonstrate that substrate inhibition arises from the rate-limiting product-release step, instead of the…

Salts modulate the behavior of intrinsically disordered proteins (IDPs) and influence the formation of membraneless organelles through liquid-liquid phase separation (LLPS). In low ionic strength solutions, IDP conformations are perturbed by the screening of electrostatic interactions, independent of the salt identity. In this regime, insight into the IDP behavior can be obtained using the theory for salt-induced transitions in charged polymers. However, salt-specific interactions with the charged and uncharged residues, known as the Hofmeister effect, influence IDP behavior in high ionic strength solutions. There is a lack of reliable theoretical models in high salt concentration regimes to predict the salt effect on IDPs. We propose a simulation methodology using a coarse-grained IDP model and experimentally measured water to salt solution transfer free energies of various chemical groups that allowed us to study the salt-specific transitions induced in the IDPs conformational ensemble. We probed the effect of three different monovalent salts on five IDPs belonging to various…

The association of ions describes the formation of ion species in electrolyte solutions and is strongly related to the salt concentration. However, the discussion of ion species and their transport is ambiguous in some studies on electrolyte materials due to the assumption of ideal solutions. Accordingly, in this work, molecular dynamics simulations are used to study ion association and transport properties of poly(ethylene)oxide (PEO)–lithium bis(trifluoromethanesulfonyl)imide electrolytes over a range of salt concentrations ( r = [Li]/[EO]) from 0.01 to 0.20. Based on the analysis of the solvation environment and ion species, it is revealed that the distinct ion–ion correlations exist in two different characteristic areas, with a salt concentration of 0.10 as the limit. Below the critical concentration, the dynamic equilibrium between free ions and ion pairs is the most important process affecting the transport properties of electrolytes, but the process may have a minor influence on the applicability of the Nernst–Einstein relation. In concentrated solutions, a large number of…

ions to enter cells, resulting in a signal of cell apoptosis. Hence, one might think that oligomers are more toxic due to their higher ability to create ion channels than fibrils. In this work, we study the effect of Aβ42 dodecamer and fibrils on a neuronal membrane, which is similar to that observed in AD patients, using all-atom molecular dynamics simulations. Due to short simulation times, we cannot observe the formation of pores, but useful insight on the early events of this process has been obtained. Namely, we showed that dodecamer distorts the lipid membrane to a greater extent than fibrils, which may indicate that ion channels can be more easily formed in the presence of oligomers. Based on this result, we anticipate that oligomers are more toxic than mature fibrils, as observed experimentally. Moreover, the Aβ-membrane interaction was found to be governed by the repulsive electrostatic interaction between Aβ and the ganglioside GM1 lipid. We calculated the bending and compressibility modulus of the membrane in the absence of Aβ and obtained good agreement with the…

From ab initio simulations of liquid water, the time-dependent friction functions and time-averaged nonlinear effective bond potentials for the OH stretch and HOH bend vibrations are extracted. The obtained friction exhibits not only adiabatic contributions at and below the vibrational time scales but also much slower nonadiabatic contributions, reflecting homogeneous and inhomogeneous line broadening mechanisms, respectively. Intermolecular interactions in liquid water soften both stretch and bend potentials compared to the gas phase, which by itself would lead to a red-shift of the corresponding vibrational bands. In contrast, nonadiabatic friction contributions cause a spectral blue shift. For the stretch mode, the potential effect dominates, and thus, a significant red shift when going from gas to the liquid phase results. For the bend mode, potential and nonadiabatic friction effects are of comparable magnitude, so that a slight blue shift results, in agreement with well-known but puzzling experimental findings. The observed line broadening is shown to be roughly equally caused…

Structure-based drug design (SBDD) is a prominent method in rational drug development and has traditionally benefitted from the atomic models of protein targets obtained using X-ray crystallography at cryogenic temperatures. In this perspective, we highlight recent advances in the development of structural techniques that are capable of probing dynamic information about protein targets. First, we discuss advances in the field of X-ray crystallography including serial room-temperature crystallography as a method for obtaining high-resolution conformational dynamics of protein-inhibitor complexes. Next, we look at cryogenic electron microscopy (cryoEM), another high-resolution technique that has recently been used to study proteins and protein complexes that are too difficult to crystallize. Finally, we present small-angle X-ray scattering (SAXS) as a potential high-throughput screening tool to identify inhibitors that target protein complexes and protein oligomerization.

Accurate calculation of the binding free energies between a protein and a ligand is the primary objective of structure-based drug design, but it still remains a challenging problem. In this work, we apply the screening molecular mechanics/Poisson Boltzmann surface area (MM/PBSA) method to calculate the binding affinity of protein-ligand interactions. Our results show that the performance of the screening MM/PBSA is better than that of the standard MM/PBSA, especially in a charged-ligand system. In addition, we also investigate the effect of the solute dielectric constant on the results, and find that the optimal solute dielectric constants are different between the neutral-ligand system and the charged-ligand system. Moreover, we also evaluate the effect of the atomic-charge methods on the performance of the screening MM/PBSA. The present study demonstrates that the screening MM/PBSA should be a reliable method for calculating binding energy of biosystems.

This Mini-Review Article outlines recent advances in the study of local electric field (LEF) governed enzyme catalysis and the application of the LEF principle in synthetic catalyst design. We start by discussing the electrostatics principles that drive enzyme catalysis, and its experimental verifications through vibrational Stark spectroscopy. Subsequently, we describe aspects of LEFs other than catalysis, i.e., induction of mechanistic crossovers, among others. Here, we focus on the early work done using computational tools, along with some recent contributions. Following an in-depth discussion of the role of LEFs in enzyme catalysis, we then highlight some recent works on designed local electric fields (D-LEF) and their applications in organic synthesis. Subsequently, we turn to D-LEFs in synthetic enzymes and supramolecular systems (cf. the work by the Head-Gordon group). We end by discussing some of the software packages that have been developed to analyze local electric fields computationally. Overall, the present Mini-Review Article paints an insightful picture of the current…

Superconcentrated electrolytes have emerged as a promising class of materials for energy storage devices, with evidence that high voltage performance is possible even with water as the solvent. Here, we study the changes in the water hydrogen bonding network induced by the dissolution of lithium bis(trifluoromethane sulfonyl)imide (LiTFSI) in concentrations ranging from the dilute to the superconcentrated regimes. Using time-resolved two-dimensional infrared spectroscopy, we observe the progressive disruption of the water–water hydrogen bond network and the appearance of isolated water molecules interacting only with ions, which can be identified and spectroscopically isolated through the intermolecular cross-peaks between the water and the TFSI – ions. Analyzing the vibrational relaxation of excitations of the H 2 O stretching mode, we observe a transition in the dominant relaxation path as the bulk-like water vanishes and is replaced by ion-solvation water with the rapid single-step relaxation of delocalized stretching vibrations into the low frequency modes being replaced by…

Thermally induced shape memory poly(ε-caprolactone) (PCL)-based polymers are one of the most extensively researched families of biocompatible materials. They are degradable under physiological conditions and have high applicability in general biomedical engineering, with cross-linked PCL networks being particularly useful for tissue engineering. In this study, we used the optimized potentials for liquid simulations (OPLS) force field, which is well suited for describing intermolecular interactions in biomolecules, and the class II polymer consistent force field (PCFF) to investigate the properties of telechelic PCL with diacrylates as reactive functionalities on its end groups. PCFF has been specifically parameterized for simulating synthetic polymeric materials. We compare the findings of all-atom molecular dynamics simulations with known experimental data and theoretical assumptions to verify the applicability of both these force fields. We estimated the melt density, volume, transition temperatures, and mechanical characteristics of two-branched PCL diacrylates with a molecular…

The bulk viscosity, a transport coefficient in the Navier-Stokes equation, is often neglected in the continuum mechanics of Newtonian fluids. Recently, however, the role of the bulk viscosity is highlighted in the area of surface and interface-related phenomena, in systematic model up-scaling and as an important quantity for the interpretation of acoustic sensor data. The prediction of the bulk viscosity usually employs molecular dynamics and the Green-Kubo linear response theory, which is used to sample transport properties in general from molecular trajectories. Since simulations are usually carried out at specified state points in concert with the evaluation of other thermodynamic properties, the role of thermostats in molecular dynamics needs to be explored systematically. In this work, we carefully investigate the role of thermostatting schemes and numerical implementations of the Green-Kubo formalism, in particular in the canonical ensemble, using two popular water force field models. It turns out that the sampling of the bulk and shear viscosities is a delicate challenge…

To fulfill the increasing demand for drinking water, researchers are currently exploring nanoporous two-dimensional materials, such as hexagonal boron nitride (hBN), as potential desalination membranes. A prominent, yet unsolved challenge is to understand how such membranes will perform in the presence of defects or surface charge in the membrane material. In this work, we study the effect of grain boundaries (GBs) and interfacial electrostatic interactions on the desalination performance of bicrystalline nanoporous hBN using classical molecular dynamics simulations supported by quantum–mechanical density functional theory (DFT) calculations. We investigate three different nanoporous bicrystalline hBN configurations, with symmetric tilt GBs having misorientation angles of 13.2, 21.8, and 32.2°. Using lattice dynamics calculations, we find that grain boundaries alter the areas and shapes of nanopores in bicrystalline hBN, as compared to the nanopores in monocrystalline hBN. We observe that, although bicrystalline nanoporous hBN with a misorientation angle of 13.2° shows an improved…

Proteins function close to native and near-native conformations. These states are evolutionarily selected to ensure the effect of mutations is minimized. The structural organization of a protein is hierarchical and modular, which reduces the dimensionality of the configurational space of the native states. Thus, finding appropriate descriptors that define the native state among all possible states of a protein is a problem of immense interest. The present study explores the correlation between solvent accessible surface areas (SASAs) and different intraprotein as well as protein–water hydrogen bonds of 55 single-chain globular proteins from four different structural classes (all α, all β, α+β, and α/β), 16 multichain proteins, and 4 macromolecular complexes. A systematic analysis of the solvent accessible surface area and intraprotein and protein–water hydrogen bonds suggests a linear relationship between SASAs and hydrogen bonds. The number of protein–water hydrogen bonds per unit SASA ranges from 3 to 4 for all the different structural protein classes. In contrast, the number of…

Torsion and Lennard-Jones parameters of the optimized potentials for liquid simulations (OPLS) all-atom force field have been refined for describing thermodynamics and dynamics of a wide range of liquid alkanes. Monte Carlo statistical mechanics (MC) and molecular dynamics (MD) simulations were carried out. For thermodynamics properties, MC simulations with truncated electrostatic interactions performed very closely to MD simulations with a Verlet neighbor list and the particle mesh Ewald algorithm. The average errors in comparison with experimental data for computed properties were improved with the modified force field (OPLS/2020), especially for long-chain alkanes. For liquid densities, heats of vaporization, and free energies of hydration, the average errors are 0.01 g/cm 3, 0.2 kcal/mol, and ca . 0.5 kcal/mol, respectively; significant gains were made for relative heats of vaporization of isomeric series. Results for self-diffusion coefficients also reproduce experimental data well for linear alkane liquids up to hexadecane. The new force field is suitable for use in improved…

Molecular dynamics studies have demonstrated that molecular water at an interface, with either a gas or a solid, displays anisotropic orientational behavior in contrast to its bulk counterpart. This effect has been recently implicated in the like-charge attraction problem for colloidal particles in solution. Here, negatively charged particles in solution display a long-ranged attraction where continuum electrostatic theory predicts monotonically repulsive interactions, particularly in solutions with monovalent salt ions at low ionic strength. Anisotropic orientational behavior of solvent molecules at an interface gives rise to an excess interfacial electrical potential which we suggest generates an additional solvation contribution to the total free energy that is traditionally overlooked in continuum descriptions of interparticle interactions in solution. In the present investigation we perform molecular dynamics simulation based calculations of the interfacial potential using realistic surface models representing various chemistries as well as different solvents. Similar to…

The exposure of nanoparticles (NPs) to biofluids leads to the rapid coverage of proteins, named protein corona, which alters the NPs' chemicophysical and biological properties. Fundamental studies of the protein corona are thus critical to the increasing applications of NPs in nanotechnology and nanomedicines. The present work utilizes multiscale simulations of a model biological system, small ovispirin-1 peptides, and bare silver nanoparticles (AgNPs) to examine the NPs' size and surface hydrophilicity effects on formation dynamics and the structure of the peptide corona. Our simulations revealed the different adsorption dynamics of ovispirin-1 peptides on the NPs, including the direct adsorption of a single peptide and peptide aggregates and multistep adsorption, as well as an intermediate cycle of desorption and readsorption. Notably, the whole process of peptide adsorption on hydrophilic AgNP surfaces can be generalized as three stages: diffusion to the surface, initial landing via hydrophilic residues, and the final attachment. The decrease in AgNP's size leads to faster…