Diphenylhexatriene membrane probes DPH and TMA-DPH: A comparative molecular dynamics simulation study.

Fluorescence spectroscopy and microscopy have been utilized as tools in membrane biophysics for decades now. Because phospholipids are non-fluorescent, the use of extrinsic membrane probes in this context is commonplace. Among the latter, 1,6-diphenylhexatriene (DPH) and its trimethylammonium derivative (TMA-DPH) have been extensively used. It is widely believed that, owing to its additional charged group, TMA-DPH is anchored at the lipid/water interface and reports on a bilayer region that is distinct from that of the hydrophobic DPH. In this study, we employ atomistic MD simulations to characterize the behavior of DPH and TMA-DPH in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and POPC/cholesterol (4:1) bilayers. We show that although the dynamics of TMA-DPH in these membranes is noticeably more hindered than that of DPH, the location of the average fluorophore of TMA-DPH is only ~3-4Å more shallow than that of DPH. The hindrance observed in the translational and rotational motions of TMA-DPH compared to DPH is mainly not due to significant differences in depth, but to the favorable electrostatic interactions of the former with electronegative lipid atoms instead. By revealing detailed insights on the behavior of these two probes, our results are useful both in the interpretation of past work and in the planning of future experiments using them as membrane reporters.

Influence of the sterol aliphatic side chain on membrane properties: a molecular dynamics study.

Following a recent experimental investigation of the effect of the length of the alkyl side chain in a series of cholesterol analogues (Angew. Chem., Int. Ed., 2013, 52, 12848-12851), we report here an atomistic molecular dynamics characterization of the behaviour of methyl-branched side chain sterols (iso series) in POPC bilayers. The studied sterols included androstenol (i-C0-sterol) and cholesterol (i-C8-sterol), as well as four other derivatives (i-C5, i-C10, i-C12 and i-C14-sterol). For each sterol, both subtle local effects and more substantial differential alterations of membrane properties along the iso series were investigated. The location and orientation of the tetracyclic ring system is almost identical in all compounds. Among all the studied sterols, cholesterol is the sterol that presents the best matching with the hydrophobic length of POPC acyl chains, whereas longer-chained sterols interdigitate into the opposing membrane leaflet. In accordance with the experimental observations, a maximal ordering effect is observed for intermediate sterol chain length (i-C5, cholesterol, i-C10). Only for these sterols a preferential interaction with the saturated sn-1 chain of POPC (compared to the unsaturated sn-2 chain) was observed, but not for either shorter or longer-chained derivatives. This work highlights the importance of the sterol alkyl chain in the modulation of membrane properties and lateral organization in biological membranes.

A DFT study on the adsorption of benzodiazepines to vermiculite surfaces.

Widespread use of pharmaceuticals such as benzodiazepines has been resulting over the last decades in the dissemination of residues of these compounds in the environment, and such fact has been raising increasing concern. The generally low efficiencies of conventional wastewater treatment processes for the removal of this type of pollutants demands for the development of alternative or complementary water and wastewater treatment technologies, among which adsorption processes have been gaining popularity, provided that cheap efficient adsorbents are found. Clay materials have been one of the popular choices in this regard. In the present study, quantum chemical calculations have been performed by periodic DFT using the projector augmented-wave (PAW) method to characterize the interactions of two benzodiazepine molecules, alprazolam and diazepam, with a surface of clay mineral, vermiculite. It was observed that both molecules interact strongly with the vermiculite surface, both through a water-bridge binding and by cation-bridge provided by the exchangeable Mg(2+) cations of the vermiculite surface. The results point to an interesting potential of vermiculite to be used efficiently as filter medium to remove these pollutants from water and wastewater.

NBD-labeled cholesterol analogues in phospholipid bilayers: insights from molecular dynamics.

Nitrobenzoxadiazole (NBD)-labeled sterols are commonly used as fluorescent cholesterol analogues in membrane biophysics. However, some experimental reports have questioned their ability to emulate the behavior of cholesterol in phospholipid bilayers. For the purpose of a detailed clarification of this matter, atomistic molecular dynamics simulations of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayers, containing either cholesterol or one of two fluorescent cholesterol analogues, 22-NBD-cholesterol or 25-NBD-cholesterol, were carried out. It is found that these sterol probes tend to adopt conformations in which their tail-labeled fluorophore is oriented toward the lipid/water interface, with a location similar to that observed in molecular dynamics simulations of other NBD probes. This implies that in these molecules the long sterol axis is no longer aligned with the membrane normal, and preferentially adopts orientations approximately parallel to the bilayer plane. In turn, these stretched conformations, together with NBD-POPC atomic interactions, lead to slowed-down lateral diffusion of both fluorescent sterols, compared to cholesterol. From computation of the deuterium order parameter and acyl chain tilts of POPC chains for varying POPC-sterol distance, it is observed that the local ordering effect of sterol is altered in both fluorescent derivatives. In agreement with reported experimental data, both fluorescent sterols are able to increase the order of POPC at 20 mol % concentration (as some molecules adopt an upright conformation, possibly related to formation of transbilayer aggregates), albeit to a smaller extent to that of cholesterol. Altogether, this study indicates that both 22- and 25-NBD-cholesterol are unable to mimic the most important features of cholesterol's behavior in lipid bilayers.

Behavior of fluorescent cholesterol analogues dehydroergosterol and cholestatrienol in lipid bilayers: a molecular dynamics study.

Molecular dynamics simulations of bilayer systems consisting of varying proportions of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), cholesterol (Chol), and intrinsically fluorescent Chol analogues dehydroergosterol (DHE) or cholestatrienol (CTL) were carried out to study in detail the extent to which these fluorescent probes mimic Chol's behavior (location, orientation, dynamics) in membranes as well as their effect on host bilayer structure and dynamics (namely their ability to induce membrane ordering in comparison with Chol). Control properties of POPC and POPC/Chol bilayers agree well with published experimental and simulation work. Both probes and Chol share similar structural and dynamical properties within the bilayers. Additionally, the fluorescent sterols induce membrane ordering to a similar (slightly lower) extent to that of Chol. These findings combined demonstrate that the two studied fluorescent sterols are adequate analogues of Chol, and may be used with advantage over side-chain labeled sterols. The small structural differences between the three studied sterols are responsible for the slight variations in the calculated properties, with CTL presenting a more similar behavior to Chol (correlating with its larger structural similarity to Chol) compared to DHE.

Switchable nonlinear optical properties of η5-monocyclopentadienylmetal complexes: a DFT approach.

Density functional theory (DFT) calculations have been carried out to investigate the switching of the second-order nonlinear optical (NLO) properties of η(5)-monocyclopentadienyliron(II) and ruthenium(II) model complexes presenting 5-(3-(thiophen-2-yl)benzo[c]thiophen-1-yl)thiophene-2-carbonitrile as a ligand. The switching properties were induced by redox means. Both oxidation and reduction stimulus have been considered, and calculations have been performed both for the complexes and for the free benzo[c]thiophene derivative ligand in order to elucidate the role played by the organometallic fragment on the second-order NLO properties of these complexes. B3LYP, CAM-B3LYP, and M06 functionals were used for our calculations. The results show some important structural changes upon oxidation/reduction that are accompanied by significant differences on the corresponding second-order NLO properties. TD-DFT calculations show that these differences on the second-order NLO response upon oxidation/reduction are due to a change in the charge transfer pattern, in which the organometallic iron and ruthenium moieties play an important role. The calculated static hyperpolarizabilities were found to be strongly functional dependent. CAM-B3LYP, however, seems to predict more reliable structural and optical data as well as hyperpolarizabilities when compared to experimental data. The use of this functional predicts that the studied complexes can be viewed as acting as redox second-order NLO switches, in particular using oxidation stimulus. The ß(tot) value of one-electron oxidized species is at least ~8.3 times (for Ru complex) and ~5.5 times (for Fe complex) as large as that of its nonoxidized counterparts.

Molecular dynamics simulations of T-20 HIV fusion inhibitor interacting with model membranes.

T-20 (also known as enfuvirtide) is a fusion inhibitor peptide known to have some effectiveness in the control of progression of HIV infection by inhibiting the fusion of the HIV envelope with the target cell membrane. Recent results indicate that T-20 is able to interact with membranes in the liquid disordered state but not with membranes in an ordered state, which could be linked to its effectiveness. A detailed molecular picture of the interaction of these molecules with membranes is still lacking. To this effect, extensive molecular dynamics simulations (100 ns) were carried out to investigate the interaction between T-20 and bilayers of 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) and POPC/cholesterol (1:1). Membrane properties such as area/lipid, density profiles, order parameters and membrane thickness were studied. It was observed that T-20 has the ability to interact to different extents with both model membranes in this study and that peptide interaction with the bilayer surface has a local effect on membrane structure. The formation of hydrogen bonding between certain peptide residues and the POPC phosphate group was observed. However, T-20 showed a more limited extent of interaction with model membranes when compared with other, more efficient, peptides (such as T-1249). This effect is most notable in POPC/Chol membranes in which interaction is especially weak, owing to less peptide residues acting as H bond donors to POPC and virtually no H bonds being formed between T-20 and cholesterol. This lower ability to interact with membranes is probably correlated with its smaller inhibitory efficiency.

Excess thermodynamic properties of mixtures involving xenon and light alkanes: a study of their temperature dependence by computer simulation.

As a natural extension of a previous work, excess molar enthalpies and excess molar volumes as a function of composition in a wide range of temperatures have been obtained for binary mixtures of xenon with ethane, propane, and n-butane by Monte Carlo computer simulation. Xenon was modeled by a simple spherical Lennard-Jones potential, and the TraPPE-UA force field was used to describe the n-alkanes. One of the main goals of this study is to investigate the temperature dependence of the excess properties for mixtures of xenon and n-alkanes and, if possible, to supplement the lack of experimental data. For all three systems, the simulation results predicted excess volumes in good agreement with the experimental data. As for the excess enthalpies, in the case of (xenon + ethane), the simulation results confirm the negative experimental result and the weak temperature dependence. In the case of (xenon + propane) and (xenon + n-butane), however, the simulation predicts negative excess enthalpies, but those estimated from experimental data are positive. Both excess volumes and enthalpies display a complex dependence on temperature that in some aspects resembles that found for mixtures of n-alkanes.The structure of the liquid mixtures was also investigated by calculating radial distribution functions [g(αß)(r)] between each pair of interaction groups for all the binary systems at all temperatures. It is found that the mean distance between xenon and CH(2) groups is systematically higher than the distance between xenon and CH(3). In addition, the number of groups around xenon in the first coordination sphere was calculated and seems to be proportionally more populated by methyl groups than by methylene groups. The results seem to reflect a preferential and stronger interaction between xenon and CH(3), in agreement with previous findings.

Recent developments in molecular dynamics simulations of fluorescent membrane probes.

Due to their sensitivity and versatility, the use of fluorescence techniques in membrane biophysics is widespread. Because membrane lipids are non-fluorescent, extrinsic membrane probes are widely used. However, the behaviour of these probes when inserted in the bilayer is often poorly understood, and it can be hard to distinguish between legitimate membrane properties and perturbation resulting from probe incorporation. Atomistic molecular dynamics simulations present a convenient way to address these issues and have been increasingly used in recent years in this context. This article reviews the application of molecular dynamics to the study of fluorescent membrane probes, focusing on recent work with complex design fluorophores and ordered bilayer systems.

Evaluation of phosphinoamidoester-derived Pd catalysts in the asymmetric allylic alkylation reaction: theoretical studies and mechanistic insights.

Two simple hemilabile P,O-coordinating phosphinoamidoester ligands 6a and 6b were synthesized and studied in the Pd(0)-catalyzed asymmetric allylic alkylation of rac-1,3-diphenylpropenyl acetate affording a highest ee of 83% ee with 6a. To gain an insight into the actual mechanism of this catalytic reactions, which had previously been investigated with a first generation family of P,O-coordinating phosphinoamido-alcohol ligands-4a and 4b-a semiempirical computational study was carried out with the Pd-allyl complexes formed from both 4a and 6a including Hitchcock's phosphinoamido-alcohol ligand 5 (R(1)= H, R(2)= Ph). The results of this study substantiate a working model that has previously been proposed for this reaction using hemilabile P,O-coordinating phosphinoamido-type ligands.

Effects of fluorescent probe NBD-PC on the structure, dynamics and phase transition of DPPC. A molecular dynamics and differential scanning calorimetry study.

We present a combined theoretical (molecular dynamics, MD) and experimental (differential scanning calorimetry, DSC) study of the effect of 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD) acyl chain-labeled fluorescent phospholipid analogs (C6-NBD-PC and C12-NBD-PC) on 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) bilayers. DSC measurements reveal that <1 mol% of NBD-PC causes elimination of the pre-transition and a large loss of cooperativity of the main transition of DPPC. Labeling with C6-NBD-PC or C12-NBD-PC shifts the main transition temperature to lower or higher values, respectively. Following our recent report on the location and dynamics of these probes (BBA 1768 (2007) 467-478) in fluid phase DPPC, we present a detailed analysis of 100-ns MD simulations of systems containing either C6-NBD-PC or C12-NBD-PC, focused on their influence on several properties of the host bilayer. Whereas most monitored parameters are not severely affected for 1.6 mol% of probe, for the higher concentration studied (6.2 mol%) important differences are evident. In agreement with published reports, we observed that the average area per phospholipid molecule increases, whereas DPPC acyl chain order parameters decrease. Moreover, we predict that incorporation of NBD-PC should increase the electrostatic potential across the bilayer and, especially for C12-NBD-PC, slow lateral diffusion of DPPC molecules and rotational mobility of DPPC acyl chains.

Adsorption of normal pentane on the surface of rutile. Experimental results and simulations.

Adsorption isotherms and differential heats of normal pentane adsorption on microcrystalline rutile were measured at 303 K. The heat of adsorption of n-pentane on rutile at zero occupancy is 64 kJ/mol. The differential heats have three descending segments, corresponding to the adsorption of n-pentane on three types of surfaces. At low coverage (first segment), the adsorption is restricted to the rows A of the (110) faces along the 5-fold coordinatively unsaturated (cus) Ti(4+) ions with differential heat showing a linear decrease with increasing occupancy. The second segment is attributed to bonding with atoms of the rows along the remaining faces exposed, (101) and (100). The third segment is related to a multilayer adsorption. The mean molar adsorption entropy of n-pentane is ca. -25 J/mol K less than the entropy of the bulk liquid, thus revealing a hindered state of motion of the n-pentane molecules on the surface of rutile. Simulations of the adsorption of n-pentane on the three most abundant crystallographic faces of rutile were also performed. The adsorption isotherm obtained from the combination of each face's isotherm weighted by the respective abundance was found to be in a good agreement with the experimental data. A structural characterization of n-pentane near the surface was also conducted, and it was found that the substrate, especially for the (110) face, strongly perturbs the distribution of n-pentane conformations, compared to those found for the gas phase. Adsorbed molecules are predominantly oriented with their long axes and their backbone zigzag planes parallel to the surface and are also characterized by fewer gauche conformations than observed in the bulk phase.

Excess thermodynamics of mixtures involving xenon and light linear alkanes by computer simulation.

Excess molar enthalpies and excess molar volumes as a function of composition for liquid mixtures of xenon + ethane (at 161.40 K), xenon + propane (at 161.40 K) and xenon + n-butane (at 182.34 K) have been obtained by Monte Carlo computer simulations and compared with available experimental data. Simulation conditions were chosen to closely match those of the corresponding experimental results. The TraPPE-UA force field was selected among other force fields to model all the alkanes studied, whereas the one-center Lennard-Jones potential from Bohn et al. was used for xenon. The calculated H(m)(E) and V(m)(E) for all systems are negative, increasing in magnitude as the alkane chain length increases. The results for these systems were compared with experimental data and with other theoretical calculations using the SAFT approach. An excellent agreement between simulation and experimental results was found for xenon + ethane system, whereas for the remaining two systems, some deviations that become progressively more significant as the alkane chain length increases were observed.

Location and dynamics of acyl chain NBD-labeled phosphatidylcholine (NBD-PC) in DPPC bilayers. A molecular dynamics and time-resolved fluorescence anisotropy study.

100-ns molecular dynamics simulations of fluid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) bilayers, both pure and containing 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD) acyl-chain labeled fluorescent analogs (C6-NBD-PC and C12-NBD-PC), are described. These molecules are widely used as probes for lipid structure and dynamics. The results obtained here for pure DPPC agree with both experimental and theoretical published works. We verified that the NBD fluorophore of both derivatives loops to a transverse location closer to the interface than to the center of the bilayer. Whereas this was observed previously in experimental literature works, conflicting transverse locations were proposed for the NBD group. According to our results, the maximum of the transverse distribution of NBD is located around the glycerol backbone/carbonyl region, and the nitro group is the most external part of the fluorophore. Hydrogen bonds from the NH group of NBD (mostly to glycerol backbone lipid O atoms) and to the nitro O atoms of NBD (from water OH groups) are continuously observed. Rotation of NBD occurs with approximately 2.5-5 ns average correlation time for these probes, but very fast, unresolved reorientation motions occur in <20 ps, in agreement with time-resolved fluorescence anisotropy measurements. Finally, within the uncertainty of the analysis, both probes show lateral diffusion dynamics identical to DPPC.