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.

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This article reviews the different density functional theory (DFT) methods available in the literature for dealing with dispersion interactions and recent applications of DFT approaches including van der Waals corrections in the study of the interaction of atoms and molecules with several different surfaces. Focus is given to the interaction of atoms and molecules with metal, metal oxide and graphite surfaces or more complex systems. It will be shown that DFT approaches including van der Waals corrections present significant advances over standard exchange correlation functionals for treating systems dominated by weak interactions.

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.

In this article, we investigate fluid-gel transformations of a DPPC lipid bilayer in the presence of nanoparticles, using coarse-grained molecular dynamics. Two types of nanoparticles are considered, specifically a 3 nm hydrophobic nanoparticle located in the core of the bilayer and a 6 nm charged nanoparticle located at the interface between the bilayer and water phase. Both negatively and positively charged nanoparticles at the bilayer interface are investigated. We demonstrate that the presence of all types of nanoparticles induces disorder effects in the structure of the lipid bilayer. These effects are characterized using computer visualization of the gel phase in the presence of nanoparticles, radial distribution functions, and order parameters. The 3 nm hydrophobic nanoparticle immersed in the bilayer core and the positively charged nanoparticle at the bilayer surface have no effect on the temperature of the fluid-gel transformation, compared to the bulk case. Interestingly, a negatively charged hydrophobic nanoparticle located at the surface of the bilayer causes slight shift of the fluid-gel transformation to a lower temperature, compared to the bulk bilayer case.

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~3-4 Å 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.

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.

New ruthenium methyl-cyclopentadienyl compounds bearing bipyridine derivatives with the general formula [Ru(η-MeCp)(PPh)(4,4'-R-2,2'-bpy)] (Ru1, R = H; Ru2, R = CH; and Ru3, R = CHOH) have been synthesized and characterized by spectroscopic and analytical techniques. Ru1 crystallized in the monoclinic P2/ c, Ru2 in the triclinic P1̅, and Ru3 in the monoclinic P2/ n space group. In all molecular structures, the ruthenium center adopts a "piano stool" distribution. Density functional theory calculations were performed for all complexes, and the results support spectroscopic data. Ru1 and Ru3 were poor substrates of the main multidrug resistance human pumps, ABCB1, ABCG2, ABCC1, and ABCC2, while Ru2 displayed inhibitory properties of ABCC1 and ABCC2 pumps. Importantly, all compounds displayed a very high cytotoxic profile for ovarian cancer cells (sensitive and resistant) that was much more pronounced than that observed with cisplatin, making them very promising anticancer agents.