Showing papers in "Journal of Physical Chemistry B in 2017"
TL;DR: It is shown that the cationic and anionic Hofmeister series can now be rationalized primarily in terms of specific interactions of salt ions with the backbone and charged side chain groups at the protein surface in solution.
Abstract: Ions differ in their ability to salt out proteins from solution as expressed in the lyotropic or Hofmeister series of cations and anions. Since its first formulation in 1888, this series has been invoked in a plethora of effects, going beyond the original salting out/salting in idea to include enzyme activities and the crystallization of proteins, as well as to processes not involving proteins like ion exchange, the surface tension of electrolytes, or bubble coalescence. Although it has been clear that the Hofmeister series is intimately connected to ion hydration in homogeneous and heterogeneous environments and to ion pairing, its molecular origin has not been fully understood. This situation could have been summarized as follows: Many chemists used the Hofmeister series as a mantra to put a label on ion-specific behavior in various environments, rather than to reach a molecular level understanding and, consequently, an ability to predict a particular effect of a given salt ion on proteins in solutions....
421 citations
TL;DR: The quality of the 1.14*CM1A and 1.20*CM5 charge models was evaluated for calculations of free energies of hydration and offsetting adjustments are made to the partial charges for atoms in specified bond types using localized bond-charge corrections (LBCC).
Abstract: The quality of the 1.14*CM1A and 1.20*CM5 charge models was evaluated for calculations of free energies of hydration. For a set of 426 neutral molecules, 1.14*CM1A and 1.20*CM5 yield MADs of 1.26 and 1.21 kcal/mol, respectively. The 1.14*CM1A charges, which can be readily obtained for large systems, exhibit large deviations only for a subset of functional groups. The results for these cases were systematically improved using localized bond-charge corrections (LBCC) by which offsetting adjustments are made to the partial charges for atoms in specified bond types. Only 19 LBCCs were needed to yield 1.14*CM1A-LBCC charges that reduce the errors for the 426 ΔGhyd values to only 0.61 kcal/mol. The modified charge method was also tested in computation of heats of vaporization and densities for pure organic liquids, yielding average errors of 1.40 kcal/mol and 0.024 g/cm3, similar to those for 1.14*CM1A.
333 citations
TL;DR: The AMBER-FB15 protein force field was developed by building a high-quality quantum chemical data set consisting of comprehensive potential energy scans and employing the ForceBalance software package for parameter optimization, which allows for more significant thermodynamic fluctuations away from local minima.
Abstract: The increasing availability of high-quality experimental data and first-principles calculations creates opportunities for developing more accurate empirical force fields for simulation of proteins. We developed the AMBER-FB15 protein force field by building a high-quality quantum chemical data set consisting of comprehensive potential energy scans and employing the ForceBalance software package for parameter optimization. The optimized potential surface allows for more significant thermodynamic fluctuations away from local minima. In validation studies where simulation results are compared to experimental measurements, AMBER-FB15 in combination with the updated TIP3P-FB water model predicts equilibrium properties with equivalent accuracy, and temperature dependent properties with significantly improved accuracy, in comparison with published models. We also discuss the effect of changing the protein force field and water model on the simulation results.
190 citations
TL;DR: This work introduces a computational model that underwent progressive molding and fine-tuning as a result of its synergistic collaboration with numerous in vitro PAMPA permeability assays, and introduces itself as a useful, predictive tool for permeability prediction.
Abstract: Membrane permeability is a key property to consider during the drug design process, and particularly vital when dealing with small molecules that have intracellular targets as their efficacy highly depends on their ability to cross the membrane. In this work, we describe the use of umbrella sampling molecular dynamics (MD) computational modeling to comprehensively assess the passive permeability profile of a range of compounds through a lipid bilayer. The model was initially calibrated through in vitro validation studies employing a parallel artificial membrane permeability assay (PAMPA). The model was subsequently evaluated for its quantitative prediction of permeability profiles for a series of custom synthesized and closely related compounds. The results exhibited substantially improved agreement with the PAMPA data, relative to alternative existing methods. Our work introduces a computational model that underwent progressive molding and fine-tuning as a result of its synergistic collaboration with num...
167 citations
TL;DR: Computer simulations of atomistic models of concentrated peptide and protein systems at different levels of complexity are beginning to provide new insights into the effects of crowding in biological environments on biomolecular structure, dynamics, and function.
Abstract: The effects of crowding in biological environments on biomolecular structure, dynamics, and function remain not well understood. Computer simulations of atomistic models of concentrated peptide and protein systems at different levels of complexity are beginning to provide new insights. Crowding, weak interactions with other macromolecules and metabolites, and altered solvent properties within cellular environments appear to remodel the energy landscape of peptides and proteins in significant ways including the possibility of native state destabilization. Crowding is also seen to affect dynamic properties, both conformational dynamics and diffusional properties of macromolecules. Recent simulations that address these questions are reviewed here and discussed in the context of relevant experiments.
142 citations
TL;DR: Analysis of the experiments shows that for polymer beads in a dry environment, the magnitude of the IR-PHI signal is determined by the scattering cross section of the nano-object at the probe wavelength, in contrast to conventional PHI experiments in a heat-transfer medium, where the signal scales as the absorption cross section.
Abstract: Infrared (IR) imaging provides chemical-specific information without the need for exogenous labels. Conventional far-field IR imaging techniques are diffraction limited, which means an effective spatial resolution of >5 μm with currently available optics. In this article, we present a novel far-field IR imaging technique based on photothermal heterodyne imaging (IR-PHI). In our version of IR-PHI, an IR pump laser excites the sample, causing a small temperature rise that is detected by a counterpropagating visible probe beam. Images and spectra of several different types of soft matter systems (polystyrene beads, thin polymer films, and single Escherichia coli bacterial cells) are presented to demonstrate the sensitivity and versatility of the technique. Importantly, the spatial resolution in the IR-PHI measurements is determined by the visible probe beam: a spatial resolution of 0.3 μm was achieved with a 0.53 μm probe wavelength and a high numerical aperture focusing objective. This is the highest spatia...
125 citations
TL;DR: The key finding, irrespective of the force field, is that the dimer is stabilized by nonspecific interactions, explaining therefore its possible transient binding to multiple cellular partners and, in part, its toxicity.
Abstract: The dimer of the amyloid-β peptide Aβ of 42 residues is the smallest toxic species in Alzheimer's disease, but its equilibrium structures are unknown Here we determined the equilibrium ensembles generated by the four atomistic OPLS-AA, CHARMM22*, AMBER99sb-ildn, and AMBERsb14 force fields with the TIP3P water model On the basis of 144 μs replica exchange molecular dynamics simulations (with 750 ns per replica), we find that the four force fields lead to random coil ensembles with calculated cross-collision sections, hydrodynamics properties, and small-angle X-ray scattering profiles independent of the force field There are, however, marked differences in secondary structure, with the AMBERsb14 and CHARMM22* ensembles overestimating the CD-derived helix content, and the OPLS-AA and AMBER99sb-ildn secondary structure contents in agreement with CD data Also the intramolecular beta-hairpin content spanning residues 17-21 and 30-36 varies between 15% and 13% Overall, there are significant differences in tertiary and quaternary conformations among all force fields, and the key finding, irrespective of the force field, is that the dimer is stabilized by nonspecific interactions, explaining therefore its possible transient binding to multiple cellular partners and, in part, its toxicity
114 citations
TL;DR: This work unambiguously shows the structure of choline chloride-malic acid (malicine) as a liquid and also in solid and hydrated forms, using neutron total scattering on D/H isotope-substituted samples, and quasi-elastic neutron scattering (QENS).
Abstract: Little is presently known about the unique nanostructure of deep eutectic solvents (DES). The order of the liquid–solid phase transition is contended and whether DES-water mixtures are merely aqueous solutions, or have properties dominated by the eutectic pair, is unclear. Here, we unambiguously show the structure of choline chloride-malic acid (malicine) as a liquid, and also in solid and hydrated forms, using neutron total scattering on D/H isotope-substituted samples, and quasi-elastic neutron scattering (QENS). Data were refined using empirical potential structure refinement. We show evidence for a stoichiometric complex ion cluster in the disordered liquid, with strong choline–chloride bonding and a hydrogen bond donor (HBD) contribution. The 1:1 eutectic stoichiometry makes these ionic domains more well-defined, with less HBD clustering than seen previously for reline. There is minimal structural difference for the solidified material, demonstrating that this DES solidification is a glass transition...
113 citations
TL;DR: Nanocellulose extracted from wood pulps using TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl radical)-mediated oxidation and sulfuric acid hydrolyzed cellulose nanocrystal methods was characterized by small-angle neutron scattering (SANS), small-angles X-ray scattering (SAXS), and dynamic light scattering (DLS) techniques.
Abstract: Nanocellulose extracted from wood pulps using TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl radical)-mediated oxidation and sulfuric acid hydrolysis methods was characterized by small-angle neutron scattering (SANS), small-angle X-ray scattering (SAXS), and dynamic light scattering (DLS) techniques. The dimensions of this nanocellulose (TEMPO-oxidized cellulose nanofiber (TOCN) and sulfuric acid hydrolyzed cellulose nanocrystal (SACN)) revealed by the different scattering methods were compared with those characterized by transmission electron microscopy (TEM). The SANS and SAXS data were analyzed using a parallelepiped-based form factor. The width and thickness of the nanocellulose cross section were ∼8 and ∼2 nm for TOCN and ∼20 and ∼3 nm for SACN, respectively, where the fitting results from SANS and SAXS profiles were consistent with each other. DLS was carried out under both the VV mode with the polarizer and analyzer parallel to each other and the HV mode having them perpendicular to each other. Using ...
106 citations
TL;DR: eABF does not directly bias the collective coordinates of interest, but rather fictitious variables that are harmonically coupled to them, making it easily applicable to a wider range of problems than ABF, and it converges to the physical free energy surface faster than standard ABF for a wide range of parameters.
Abstract: We report a theoretical description and numerical tests of the extended-system adaptive biasing force method (eABF), together with an unbiased estimator of the free energy surface from eABF dynamics. Whereas the original ABF approach uses its running estimate of the free energy gradient as the adaptive biasing force, eABF is built on the idea that the exact free energy gradient is not necessary for efficient exploration, and that it is still possible to recover the exact free energy separately with an appropriate estimator. eABF does not directly bias the collective coordinates of interest, but rather fictitious variables that are harmonically coupled to them; therefore is does not require second derivative estimates, making it easily applicable to a wider range of problems than ABF. Furthermore, the extended variables present a smoother, coarse-grain-like sampling problem on a mollified free energy surface, leading to faster exploration and convergence. We also introduce CZAR, a simple, unbiased free energy estimator from eABF trajectories. eABF/CZAR converges to the physical free energy surface faster than standard ABF for a wide range of parameters.
100 citations
TL;DR: The comprehensive picture that emerges for the formation of oriented protein films with preserved native conformation will help guide efforts to create functional films for new technologies.
Abstract: Molecular details of BSA adsorption on a silica surface are revealed by fully atomistic molecular dynamics (MD) simulations (with a 0.5 μs trajectory), supported by dynamic light scattering (DLS), zeta potential, multiparametric surface plasmon resonance (MP-SPR), and contact angle experiments. The experimental and theoretical methods complement one another and lead to a wider understanding of the mechanism of BSA adsorption across a range of pH 3–9. The MD results show how the negatively charged BSA at pH7 adsorbs to the negatively charged silica surface, and reveal a unique orientation with preserved secondary and tertiary structure. The experiments then show that the protein forms complete monolayers at ∼ pH6, just above the protein’s isoelectric point (pH5.1). The surface contact angle is maximum when it is completely coated with protein, and the hydrophobicity of the surface is understood in terms of the simulated protein conformation. The adsorption behavior at higher pH > 6 is also consistently int...
TL;DR: The use of replica-exchange umbrella sampling starting from different initial conditions as a robust approach for calculation of the binding energies in membrane simulations is proposed, revealing previously unnoticed complexities of the dimerization free energy landscape.
Abstract: Potential of mean force (PMF) calculations are used to characterize the free energy landscape of protein–lipid and protein–protein association within membranes. Coarse-grained simulations allow binding free energies to be determined with reasonable statistical error. This accuracy relies on defining a good collective variable to describe the binding and unbinding transitions, and upon criteria for assessing the convergence of the simulation toward representative equilibrium sampling. As examples, we calculate protein–lipid binding PMFs for ANT/cardiolipin and Kir2.2/PIP2, using umbrella sampling on a distance coordinate. These highlight the importance of replica exchange between windows for convergence. The use of two independent sets of simulations, initiated from bound and unbound states, provide strong evidence for simulation convergence. For a model protein–protein interaction within a membrane, center-of-mass distance is shown to be a poor collective variable for describing transmembrane helix–helix ...
TL;DR: In this article, a computational framework that is able to describe general many-body coarse-grained (CG) interactions of molecules and use it to model the free energy surface of molecular liquids as a cluster expansion in terms of monomer, dimer, and trimer terms is introduced.
Abstract: We introduce a computational framework that is able to describe general many-body coarse-grained (CG) interactions of molecules and use it to model the free energy surface of molecular liquids as a cluster expansion in terms of monomer, dimer, and trimer terms. The contributions to the free energy due to these terms are inferred from all-atom molecular dynamics (MD) data using Gaussian Approximation Potentials, a type of machine-learning model that employs Gaussian process regression. The resulting CG model is much more accurate than those possible using pair potentials. Though slower than the latter, our model can still be faster than all-atom simulations for solvent-free CG models commonly used in biomolecular simulations.
TL;DR: The periodic PSD model is tested using the coarse-grained Martini and all-atom CHARMM36 (C36) force fields and a Bayesian method for extrapolating diffusion constants of lipids and proteins in membranes obtained from simulation to infinite system size is provided.
Abstract: The periodic Saffman–Delbruck (PSD) model, an extension of the Saffman–Delbruck model developed to describe the effects of periodic boundary conditions on the diffusion constants of lipids and proteins obtained from simulation, is tested using the coarse-grained Martini and all-atom CHARMM36 (C36) force fields. Simulations of pure Martini dipalmitoylphosphatidylcholine (DPPC) bilayers and those with one embedded gramicidin A (gA) dimer or one gA monomer with sizes ranging from 512 to 2048 lipids support the PSD model. Underestimates of D∞ (the value of the diffusion constant for an infinite system) from the 512-lipid system are 35% for DPPC, 45% for the gA monomer, and 70% for the gA dimer. Simulations of all-atom DPPC and dioleoylphosphatidylcholine (DOPC) bilayers yield diffusion constants not far from experiment. However, the PSD model predicts that diffusion constants at the sizes of the simulation should underestimate experiment by approximately a factor of 3 for DPPC and 2 for DOPC. This likely impl...
TL;DR: It is shown that direct interactions of cosolvents with nonpolar solutes and aqueous polymers can strengthen hydrophobic interactions and can contribute to stabilizing collapsed globular structures.
Abstract: Cosolvents modulate aqueous solubility, hydrophobic interactions, and the stability and function of most proteins in the living cell. Our molecular-level understanding of cosolvent effects is incomplete, not only at the level of complex systems such as proteins, but also at the level of very fundamental interactions that underlie the hydrophobic effect. This Feature Article discusses cosolvent effects on the aqueous solubility of nonpolar solutes, hydrophobic interactions, and hydrophobic self-assembly/collapse of aqueous polymers, recently studied with molecular dynamics simulations. It is shown that direct interactions of cosolvents with nonpolar solutes and aqueous polymers can strengthen hydrophobic interactions and can contribute to stabilizing collapsed globular structures. The molecular-level explanation of these observations requires a better understanding of the entropy associated with fluctuations of attractive solute–solvent interactions and of length-scale dependencies of this quantity.
TL;DR: In this article, a detailed insight into how diffusion depends on protein-protein contacts is presented based on extensive all-atom molecular dynamics simulations of concentrated villin headpiece solutions, and rotational diffusion was found to slow down more significantly than translational diffusion.
Abstract: For a long time, the effect of a crowded cellular environment on protein dynamics has been largely ignored. Recent experiments indicate that proteins diffuse more slowly in a living cell than in a diluted solution, and further studies suggest that the diffusion depends on the local surroundings. Here, detailed insight into how diffusion depends on protein–protein contacts is presented based on extensive all-atom molecular dynamics simulations of concentrated villin headpiece solutions. After force field adjustments in the form of increased protein–water interactions to reproduce experimental data, translational and rotational diffusion was analyzed in detail. Although internal protein dynamics remained largely unaltered, rotational diffusion was found to slow down more significantly than translational diffusion as the protein concentration increased. The decrease in diffusion is interpreted in terms of a transient formation of protein clusters. These clusters persist on sub-microsecond time scales and fol...
TL;DR: Investigation of two deep eutectic solvents constituted of salt choline chloride along with HB donors urea and glycerol in 1:2 mol ratio finds that while TFE may interstitially accommodate itself within H-bonded network of reline, it does appear to form H-Bonds with the constituents of the glyceline.
Abstract: Deep eutectic solvents (DESs) have emerged as nontoxic and inexpensive alternatives not only to the common organic solvents but to the ionic liquids as well. Some of the common and popular, and perhaps the most investigated, DESs are the ones comprising an ammonium salt and an appropriate hydrogen bond (HB) donor in a predetermined mole ratio. The formation of the DES is attributed to the H-bonding interaction(s) present between the salt and the HB donor. Consequently, addition of a predominantly HB donor or a predominantly HB acceptor cosolvent to such DESs may result in intriguing features and properties. We present investigation of two DESs constituted of salt choline chloride along with HB donors urea and glycerol, respectively, in 1:2 mol ratio, named reline and glyceline as the cosolvent of very high HB donating acidity and no HB accepting basicity 2,2,2-trifluoroethanol (TFE) and of very high HB accepting basicity and no HB donating acidity hexamethylphosphoramide (HMPA), respectively, is added. TF...
TL;DR: On the basis of the results, it is shown that ReaxFF provides a novel approach to study the complex acid-base chemical reactions in aqueous solution with any pH value.
Abstract: Hydronium (H3O+) and hydroxide (OH–) ions have anomalously large diffusion constants in aqueous solutions due to their combination of vehicular and Grotthuss hopping diffusion mechanisms. An improvement of the ReaxFF reactive water force field on the basis of our first-generation water force field (water-2010) is presented to describe the proton transfer (PT) mechanisms of H3O+ and OH– in water. Molecular dynamics simulation studies with the water-2017 force field support the Eigen–Zundel–Eigen mechanism for PT in acidic aqueous solution and reproduce the hypercoordinated solvation structure of the OH– in a basic environment. In particular, it predicts the correct order of the diffusion constants of H2O, H3O+, and OH– and their values are in agreement with the experimental data. Another interesting observation is that the diffusion constants of H3O+ and OH– are close to each other at high concentration due to the strong correlation between OH– ions in basic aqueous solution. On the basis of our results, i...
TL;DR: The Simulation Enabled Estimation of Kinetic Rates (SEEKR) package is presented, a suite of open-source scripts and tools designed to enable researchers to perform multiscale computation of the kinetics of molecular binding, unbinding, and transport using a combination of molecular dynamics, Brownian dynamics, and milestoning theory.
Abstract: We present the Simulation Enabled Estimation of Kinetic Rates (SEEKR) package, a suite of open-source scripts and tools designed to enable researchers to perform multiscale computation of the kinetics of molecular binding, unbinding, and transport using a combination of molecular dynamics, Brownian dynamics, and milestoning theory. To demonstrate its utility, we compute the kon, koff, and ΔGbind for the protein trypsin with its noncovalent binder, benzamidine, and examine the kinetics and other results generated in the context of the new software, and compare our findings to previous studies performed on the same system. We compute a kon estimate of (2.1 ± 0.3) × 107 M-1 s-1, a koff estimate of 83 ± 14 s-1, and a ΔGbind of -7.4 ± 0.1 kcal·mol-1, all of which compare closely to the experimentally measured values of 2.9 × 107 M-1 s-1, 600 ± 300 s-1, and -6.71 ± 0.05 kcal·mol-1, respectively.
TL;DR: The first comprehensive investigation into the bulk and surface properties of IL mixtures formed from two commonly encountered ILs is presented, finding that the vacuum-IL interface is enriched significantly in C12 alkyl chains, even in mixtures low in the long-chain component.
Abstract: Ionic-liquid (IL) mixtures hold great promise, as they allow liquids with a wide range of properties to be formed by mixing two common components rather than by synthesizing a large array of pure ILs with different chemical structures. In addition, these mixtures can exhibit a range of properties and structural organization that depend on their composition, which opens up new possibilities for the composition-dependent control of IL properties for particular applications. However, the fundamental properties, structure, and dynamics of IL mixtures are currently poorly understood, which limits their more widespread application. This article presents the first comprehensive investigation into the bulk and surface properties of IL mixtures formed from two commonly encountered ILs: 1-ethyl-3-methylimidazolium and 1-dodecyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([C2mim][Tf2N] and [C12mim][Tf2N]). Physical property measurements (viscosity, conductivity, and density) reveal that these IL mixtures ...
TL;DR: This work shows experimental and simulation results demonstrating that in PolyILs Tg does not follow a universal scaling behavior with the volume of the structural units Vm (including monomer and counterion), and is significantly influenced by the chain flexibility and polymer dielectric constant.
Abstract: Polymerized ionic liquids (PolyILs) are promising candidates for a wide range of technological applications due to their single ion conductivity and good mechanical properties. Tuning the glass transition temperature (Tg) in these materials constitutes a major strategy to improve room temperature conductivity while controlling their mechanical properties. In this work, we show experimental and simulation results demonstrating that in these materials Tg does not follow a universal scaling behavior with the volume of the structural units Vm (including monomer and counterion). Instead, Tg is significantly influenced by the chain flexibility and polymer dielectric constant. We propose a simplified empirical model that includes the electrostatic interactions and chain flexibility to describe Tg in PolyILs. Our model enables design of new functional PolyILs with the desired Tg.
TL;DR: This work investigated the interactions between the gangliosides GM1 and GM3 and the proteins aquaporin (AQP1) and WALP23 using equilibrium molecular dynamics simulations and potential of mean force calculations at both coarse-grained (CG) and atomistic levels and proposed modified Martini parameters to more closely mimic the sizes and structures observed at the atomistic level.
Abstract: Gangliosides are glycolipids in which an oligosaccharide headgroup containing one or more sialic acids is connected to a ceramide. Gangliosides reside in the outer leaflet of the plasma membrane and play a crucial role in various physiological processes such as cell signal transduction and neuronal differentiation by modulating structures and functions of membrane proteins. Because the detailed behavior of gangliosides and protein-ganglioside interactions are poorly known, we investigated the interactions between the gangliosides GM1 and GM3 and the proteins aquaporin (AQP1) and WALP23 using equilibrium molecular dynamics simulations and potential of mean force calculations at both coarse-grained (CG) and atomistic levels. In atomistic simulations, on the basis of the GROMOS force field, ganglioside aggregation appears to be a result of the balance between hydrogen bond interactions and steric hindrance of the headgroups. GM3 clusters are slightly larger and more ordered than GM1 clusters due to the small...
TL;DR: This work identifies and characterizes the dual nature of salt both as plasticizer and hardener of PE assemblies and maps the interconnection of the influence of salt with the degree of hydration in the system.
Abstract: In this work, we investigate the effect of salt and water on plasticization and thermal properties of hydrated poly(diallyldimethylammonium chloride) (PDAC) and poly(sodium 4-styrenesulfonate) (PSS) assemblies via molecular dynamics simulations and modulated differential scanning calorimetry (MDSC). Commonly, both water and salt are considered to be plasticizers of hydrated polyelectrolyte assemblies. However, the simulation results presented here show that while water has a plasticizing effect, salt can also have an opposite effect on the PE assemblies. On one hand, the presence of salt ions provides additional free volume for chain motion and weakens PDAC–PSS ion pairing due to electrostatic screening, which contributes toward plasticization of the complex. On the other hand, salt ions bind water in their hydration shells, which decreases water mobility and reduces the plasticization by hydration. Our MDSC results connect the findings to macroscopic PE plasticization and the glass-transition-like therma...
TL;DR: The effectiveness of PDT in live cells with nanoclusters was demonstrated by two-photon excitation compared to one-ph photon excitation, and the implication of these results points toward new efficient two- photon 1O2 sensitizers for photodynamic therapy.
Abstract: The generation of singlet oxygen (1O2) has been established as the principal mechanism of photodynamic therapy (PDT). Various dyes, metal nanoparticles, and clusters have been shown to sensitize 1O2. However, metal nanoclusters are even more promising candidates as photosensitizers for this purpose. By understanding the optical properties that lead to efficient 1O2 generation, one can fully realize their potential as PDT photosensitizers. Three different metal nanoclusters, Au25, Ag32, and Au144, are investigated for their 1O2 generation efficiency. The Au144 showed a 1O2 generation rate that is 2 orders of magnitude higher than that for Au25 and Ag32, and several orders of magnitude higher than nanoparticles (>5 nm) due to Au144's high absorption cross section-to-volume ratio. The effectiveness of PDT in live cells with nanoclusters was demonstrated by two-photon excitation compared to one-photon excitation. The implication of these results points toward new efficient two-photon 1O2 sensitizers for photodynamic therapy.
TL;DR: It is shown that halogens acting as hydrogen bond acceptors potentially make a more favorable contribution to ligand binding than halogen bonds based on quantum mechanical calculations and bioinformatics analysis of ligand–protein crystal structures shows the presence of significant numbers of such interactions.
Abstract: Halogens are present in a significant number of drugs, contributing favorably to ligand-protein binding. Currently, the contribution of halogens, most notably chlorine and bromine, is largely attributed to halogen bonds involving favorable interactions with hydrogen bond acceptors. However, we show that halogens acting as hydrogen bond acceptors potentially make a more favorable contribution to ligand binding than halogen bonds based on quantum mechanical calculations. In addition, bioinformatics analysis of ligand-protein crystal structures shows the presence of significant numbers of such interactions. It is shown that interactions between halogens and hydrogen bond donors (HBDs) are dominated by perpendicular C-X···HBD orientations. Notably, the orientation dependence of the halogen-HBD (X-HBD) interactions is minimal over greater than 100° with favorable interaction energies ranging from -2 to -14 kcal/mol. This contrasts halogen bonds in that X-HBD interactions are substantially more favorable, being comparable to canonical hydrogen bonds, with a smaller orientation dependence, such that they make significant, favorable contributions to ligand-protein binding and, therefore, should be actively considered during rational ligand design.
TL;DR: It is found that polymer hydration is the determining factor for PNIPAM collapse in the cononsolvency regime, and it is shown that methanol frustrates the ability of water to form hydrogen bonds with the amide proton and therefore causes polymer collapse.
Abstract: We revisit the mechanism for cononsolvency of PNIPAM in water/methanol mixtures. Using extensive molecular dynamics simulations, we calculate the calorimetric enthalpy of the PNIPAM collapse transition and observe a unique fingerprint of PNIPAM cononsolvency which is analyzed in terms of microscopic interactions. We find that polymer hydration is the determining factor for PNIPAM collapse in the cononsolvency regime. In particular, it is shown that methanol frustrates the ability of water to form hydrogen bonds with the amide proton and therefore causes polymer collapse.
TL;DR: The developed fast simulation methods allow us to incorporate structural information in the decay analysis for heterogeneous cases by relating dye states with protein conformations to pave the way for fluorescence and FRET-based dynamic structural biology.
Abstract: Forster resonance energy transfer (FRET) measurements from a donor, D, to an acceptor, A, fluorophore are frequently used in vitro and in live cells to reveal information on the structure and dynamics of DA labeled macromolecules. Accurate descriptions of FRET measurements by molecular models are complicated because the fluorophores are usually coupled to the macromolecule via flexible long linkers allowing for diffusional exchange between multiple states with different fluorescence properties caused by distinct environmental quenching, dye mobilities, and variable DA distances. It is often assumed for the analysis of fluorescence intensity decays that DA distances and D quenching are uncorrelated (homogeneous quenching by FRET) and that the exchange between distinct fluorophore states is slow (quasistatic). This allows us to introduce the FRET-induced donor decay, eD(t), a function solely depending on the species fraction distribution of the rate constants of energy transfer by FRET, for a convenient joi...
TL;DR: The analysis suggests the iminium ion formation has the highest barrier and the catalytic effect of piperidine is facilitating the elimination step rather than activation of the benzaldehyde electrophile.
Abstract: The free energy profile of the piperidine catalyzed Knoevenagel condensation reaction of acetylacetone with benzaldehyde has been obtained by theoretical calculations. The carbinolamine formation step involves catalysis by methanol solvent, and its decomposition takes place via hydroxide ion elimination without a classical transition state, leading to the iminium ion. Hydroxide ion deprotonates the acetylacetone, forming an enolate that attacks the iminium ion and leads to an addition intermediate. The final step involves elimination of piperidine catalyst. Our analysis suggests the iminium ion formation has the highest barrier and the catalytic effect of piperidine is facilitating the elimination step rather than activation of the benzaldehyde electrophile. Experimental measures of the kinetics lead to an observed free energy barrier of 20.0 kcal mol–1, in good agreement with the theoretical value of 21.8 kcal mol–1 based on the free energy profile.
TL;DR: Time-resolved IR spectroscopy techniques are introduced that cover the time range from nanoseconds to minutes along with some technical considerations and an outlook toward novel experimental approaches that have the potential to provide new science.
Abstract: The catalytic activity of proteins is a function of structural changes. Very often these are as minute as protonation changes, hydrogen bonding changes, and amino acid side chain reorientations. To resolve these, a methodology is afforded that not only provides the molecular sensitivity but allows for tracing the sequence of these hierarchical reactions at the same time. This feature article showcases results from time-resolved IR spectroscopy on channelrhodopsin (ChR), light-oxygen-voltage (LOV) domain protein, and cryptochrome (CRY). All three proteins are activated by blue light, but their biological role is drastically different. Channelrhodopsin is a transmembrane retinylidene protein which represents the first light-activated ion channel of its kind and which is involved in primitive vision (phototaxis) of algae. LOV and CRY are flavin-binding proteins acting as photoreceptors in a variety of signal transduction mechanisms in all kingdoms of life. Beyond their biological relevance, these proteins ar...
TL;DR: Morphology of the conducting polymer PEDOT:TOS (poly(3,4-ethylenedioxythiophene) doped with molecular tosylate) and its crystallization in aqueous solution were studied using atomistic molecular dynamics simulations and it was found that PEDot comprises crystallite aggregates consisting of 3-6 π-π stacked chains.
Abstract: Morphology of the conducting polymer PEDOT:TOS (poly(3,4-ethylenedioxythiophene) doped with molecular tosylate) and its crystallization in aqueous solution were studied using atomistic molecular dynamics simulations. It was found that (a) PEDOT comprises crystallite aggregates consisting of 3–6 π–π stacked chains. The crystallites are linked by interpenetrating π–π stacked chains such that percolative paths in the structure are formed. (b) The size of the crystallites depends on the water content, but the π–π stacking distance is practically independent of the chain length, charge concentration and water content. (c) TOS counterions are located either on the top of the chains or on the side of the crystallites and their distribution depends on the charge concentration but is practically independent of the water content; (d) PEDOT chains and crystallites exhibit bending that depends on their length and water content.