Liposomal Copermeation Assay Reveals Unexpected Membrane Interactions of Commonly Prescribed Drugs.

The permeation of small molecules across biological membranes is a crucial process that lies at the heart of life. Permeation is involved not only in the maintenance of homeostasis at the cell level but also in the absorption and biodistribution of pharmacologically active substances throughout the human body. Membranes are formed by phospholipid bilayers that represent an energy barrier for permeating molecules. Crossing this energy barrier is assumed to be a singular event, and permeation has traditionally been described as a first-order kinetic process, proportional only to the concentration gradient of the permeating substance. For a given membrane composition, permeability was believed to be a unique property dependent only on the permeating molecule itself. We provide experimental evidence that this long-held view might not be entirely correct. Liposomes were used in copermeation experiments with a fluorescent probe, where simultaneous permeation of two substances occurred over a single phospholipid bilayer. Using an assay of six commonly prescribed drugs, we have found that the presence of a copermeant can either enhance or suppress the permeation rate of the probe molecule, often more than 2-fold in each direction. This can have significant consequences for the pharmacokinetics and bioavailability of commonly prescribed drugs when used in combination and provide new insight into so-far unexplained drug-drug interactions as well as changing the perspective on how new drug candidates are evaluated and tested.

Biodegradable Covalently Crosslinked Poly[N-(2-Hydroxypropyl) Methacrylamide] Nanogels: Preparation and Physicochemical Properties.

Recently, suitably sized polymer-based nanogels containing functional groups for the binding of biologically active substances and ultimately degradable to products that can be removed by glomerular filtration have become extensively studied systems in the field of drug delivery. Herein, we designed and tailored the synthesis of hydrophilic and biodegradable poly[N-(2-hydroxypropyl) methacrylamide-co-N,N'-bis(acryloyl) cystamine-co-6-methacrylamidohexanoyl hydrazine] (PHPMA-BAC-BMH) nanogels. The facile and versatile dispersion polymerization enabled the preparation of nanogels with a diameter below 50 nm, which is the key parameter for efficient and selective passive tumor targeting. The effects of the N,N'-bis(acryloyl) cystamine crosslinker, polymerization composition, and medium including H2O/MetCel and H2O/EtCel on the particle size, particle size distribution, morphology, and polymerization kinetics and copolymer composition were investigated in detail. We demonstrated the formation of a 38 nm colloidally stable PHPMA-BAC-BMH nanogel with a core-shell structure that can be rapidly degraded in the presence of 10 mM glutathione solution under physiologic conditions. The nanogels were stable in an aqueous solution modeling the bloodstream; thus, these nanogels have the potential to become highly important carriers in the drug delivery of various molecules.

Reliable Dimerization Energies for Modeling of Supramolecular Junctions.

Accurate estimates of intermolecular interaction energy, ΔE, are crucial for modeling the properties of organic electronic materials and many other systems. For a diverse set of 50 dimers comprising up to 50 atoms (Set50-50, with 7 of its members being models of single-stacking junctions), benchmark ΔE data were compiled. They were obtained by the focal-point strategy, which involves computations using the canonical variant of the coupled cluster theory with singles, doubles, and perturbative triples [CCSD(T)] performed while applying a large basis set, along with extrapolations of the respective energy components to the complete basis set (CBS) limit. The resulting ΔE data were used to gauge the performance for the Set50-50 of several density-functional theory (DFT)-based approaches, and of one of the localized variants of the CCSD(T) method. This evaluation revealed that (1) the proposed "silver standard" approach, which employs the localized CCSD(T) method and CBS extrapolations, can be expected to provide accuracy better than two kJ/mol for absolute values of ΔE, and (2) from among the DFT techniques, computationally by far the cheapest approach (termed "ωB97X-3c/vDZP" by its authors) performed remarkably well. These findings are directly applicable in cost-effective yet reliable searches of the potential energy surfaces of noncovalent complexes.

Lewis Acidic Aluminosilicates: Synthesis, 27Al MQ/MAS NMR, and DFT-Calculated 27Al NMR Parameters.

Porous aluminosilicates are functional materials of paramount importance as Lewis acid catalysts in the synthetic industry, yet the participating aluminum species remain poorly studied. Herein, a series of model aluminosilicate networks containing [L-AlO3] (L = THF, Et3N, pyridine, triethylphosphine oxide (TEPO)) and [AlO4]- centers were prepared through nonhydrolytic sol-gel condensation reactions of the spherosilicate building block (Me3Sn)8Si8O20 with L-AlX3 (X = Cl, Me, Et) and [Me4N] [AlCl4] compounds in THF or toluene. The substoichiometric dosage of the Al precursors ensured complete condensation and uniform incorporation, with the bulky spherosilicate forcing a separation between neighboring aluminum centers. The materials were characterized by 1H, 13C, 27Al, 29Si, and 31P MAS NMR and FTIR spectroscopies, ICP-OES, gravimetry, and N2 adsorption porosimetry. The resulting aluminum centers were resolved by 27Al TQ/MAS NMR techniques and assigned based on their spectroscopic parameters obtained by peak fitting (δiso, CQ, η) and their correspondence to the values calculated on model structures by DFT methods. A clear correlation between the decrease in the symmetry of the Al centers and the increase of the observed CQ was established with values spanning from 4.4 MHz for distorted [AlO4]- to 15.1 MHz for [THF-AlO3]. Products containing exclusively [TEPO-AlO3] or [AlO4]- centers could be obtained (single-site materials). For L = THF, Et3N, and pyridine, the [AlO4]- centers were formed together with the expected [L-AlO3] species, and a viable mechanism for the unexpected emergence of [AlO4]- was proposed.

On the Intermolecular Interactions in Thiophene-Cored Single-Stacking Junctions.

There have been attempts, both experimental and based on density-functional theory (DFT) modeling, at understanding the factors that govern the electronic conductance behavior of single-stacking junctions formed by pi-conjugated materials in nanogaps. Here, a reliable description of relevant stacked configurations of some thiophene-cored systems is provided by means of high-level quantum chemical approaches. The minimal structures of these configurations, which are found using the dispersion-corrected DFT approach, are employed in calculations that apply the coupled cluster method with singles, doubles and perturbative triples [CCSD(T)] and extrapolations to the complete basis set (CBS) limit in order to reliably quantify the strength of intermolecular binding, while their physical origin is investigated using the DFT-based symmetry-adapted perturbation theory (SAPT) of intermolecular interactions. In particular, for symmetrized S-Tn dimers (where "S" and "T" denote a thiomethyl-containing anchor group and a thiophene segment comprising "n" units, respectively), the CCSD(T)/CBS interaction energies are found to increase linearly with n ≤ 6, and significant conformational differences between the flanking 2-thiophene group in S-T1 and S-T2 are described by the CCSD(T)/CBS and SAPT/CBS computations. These results are put into the context of previous work on charge transport properties of S-Tn and other types of supramolecular junctions.

Simple Route to [PSH][B9H14] and a Contemporary Study of Its Solid-State Dynamic Behavior.

The 1,8-bis(dimethylamino)naphthalenium ([PSH]+) decaborane salt, [PSH][B10H13], has been found to react in ethanol to form [PSH][B9H14] (1), affording a simple route to the synthesis of the arachno-nonaborate anion. This new polyhedral salt is characterized by NMR spectroscopy and X-ray diffraction. The measurement of diffusion coefficients by NMR methods demonstrates that the [PSH]+ cation and the [B9H14]- anion form ion pairs in a non-coordinating solvent such as CH2Cl2, whereas in CD3CN the formation of ion pairs was not observed. Insights into the long-known low-energy dynamic behavior, which involves the bridging and endo-terminal hydrogen atoms, are elucidated using DFT calculations. Salts [PSH][B9H14] (1) and [PSH][B9H14]·0.5CHCl3 (solvated, 1·0.5CHCl3) have also been studied by X-ray diffraction analysis. A solid-state NMR study has demonstrated that K[B9H14] and [PSH][B9H14] (1) undergo significantly different motion regimes, being a low-energy, weakly temperature-dependent process for 1, which may be ascribed to some type of low-amplitude reorientation of the whole boron cages. This process may be the mechanism for the low- to-room-temperature order-disorder hidden transition found by X-ray analysis.

Quantifying the Intrinsic Strength of C-H⋯O Intermolecular Interactions.

It has been recognized that the C-H⋯O structural motif can be present in destabilizing as well as highly stabilizing intermolecular environments. Thus, it should be of interest to describe the strength of the C-H⋯O hydrogen bond for constant structural factors so that this intrinsic strength can be quantified and compared to other types of interactions. This description is provided here for C2h-symmetric dimers of acrylic acid by means of the calculations that employ the coupled-cluster theory with singles, doubles, and perturbative triples [CCSD(T)] together with an extrapolation to the complete basis set (CBS) limit. Dimers featuring the C-H⋯O and O-H⋯O hydrogens bonds are carefully investigated in a wide range of intermolecular separations by the CCSD(T)/CBS approach, and also by the symmetry-adapted perturbation theory (SAPT) method, which is based on the density-functional theory (DFT) treatment of monomers. While the nature of these two types of hydrogen bonding is very similar according to the SAPT-DFT/CBS calculations and on the basis of a comparison of the intermolecular potential curves, the intrinsic strength of the C-H⋯O interaction is found to be about a quarter of its O-H⋯O counterpart that is less than one might anticipate.

RAFT Polymerisation and Hypercrosslinking Improve Crosslink Homogeneity and Surface Area of Styrene Based PolyHIPEs.

The influence of a polymerisation mechanism (reversible addition-fragmentation chain transfer; RAFT vs. free radical polymerisation; FRP) on the porous structure of highly porous poly(styrene-co-divinylbenzene) polymers was investigated. The highly porous polymers were synthesised via high internal phase emulsion templating (polymerizing the continuous phase of a high internal phase emulsion), utilising either FRP or RAFT processes. Furthermore, residual vinyl groups in the polymer chains were used for the subsequent crosslinking (hypercrosslinking) applying di-tert-butyl peroxide as the source of radicals. A significant difference in the specific surface area of polymers prepared by FRP (between 20 and 35 m2/g) and samples prepared by RAFT polymerisation (between 60 and 150 m2/g) was found. Based on the results from gas adsorption and solid state NMR, it could be concluded that the RAFT polymerisation affects the homogeneous distribution of the crosslinks in the highly crosslinked styrene-co-divinylbenzene polymer network. During the initial crosslinking, RAFT polymerisation leads to the increase in mesopores with diameters between 2 and 20 nm, resulting in good accessibility of polymer chains during the hypercrosslinking reaction, which is reflected in increased microporosity. The fraction of micropores created during the hypercrosslinking of polymers prepared via RAFT is around 10% of the total pore volume, which is up to 10 times more than for polymers prepared by FRP. Specific surface area, mesopore surface area, and total pore volume after hypercrosslinking reach almost the same values, regardless of the initial crosslinking. The degree of hypercrosslinking was confirmed by determination of the remaining double bonds by solid-state NMR analysis.

Combining Polymerization and Templating toward Hyper-Cross-Linked Poly(propargyl aldehyde)s and Poly(propargyl alcohol)s for Reversible H2O and CO2 Capture and Construction of Porous Chiral Networks.

Two series of hyper-cross-linked microporous polyacetylene networks containing either -[CH=C(CH=O)]- or -[CH=C(CH2OH)]- monomeric units are reported. Networks are prepared by chain-growth copolymerization of acetal-protected propargyl aldehyde and acetal-protected propargyl alcohol with a 1,3,5-triethynylbenzene cross-linker followed by hydrolytic deprotection/detemplating. Deprotection not only liberates reactive CH=O and CH2OH groups in the networks but also modifies the texture of the networks towards higher microporosity and higher specific surface area. The final networks with CH=O and CH2OH groups attached directly to the polyene main chains of the networks have a specific surface area from 400 to 800 m2/g and contain functional groups in a high amount, up to 9.6 mmol/g. The CH=O and CH2OH groups in the networks serve as active centres for the reversible capture of CO2 and water vapour. The water vapour capture capacities of the networks (up to 445 mg/g at 297 K) are among the highest values reported for porous polymers, making these materials promising for cyclic water harvesting from the air. Covalent modification of the networks with (R)-(+)-3-aminopyrrolidine and (S)-(+)-2-methylbutyric acid enables the preparation of porous chiral networks and shows networks with CH=O and CH2OH groups as reactive supports suitable for the anchoring of various functional molecules.

Adsorption and Release Properties of Drug Delivery System Naproxen-SBA-15: Effect of Surface Polarity, Sodium/Acid Drug Form and pH.

Mesoporous silica SBA-15 was prepared via sol-gel synthesis and functionalized with different types of organosilanes containing various organic functional groups: (3-aminopropyl)triethoxysilane (SBA-15-NH2), (3-mercaptopropyl)triethoxysilane (SBA-15-SH), triethoxymethylsilane (SBA-15-CH3), triethoxyphenylsilane (SBA-15-Ph), and (3-isocynatopropyl)triethoxysilane (SBA-15-NCO). The prepared materials were investigated as drug delivery systems for naproxen. As model drugs, naproxen acid (HNAP) and its sodium salt (NaNAP) were used. Mentioned medicaments belong to the group of non-steroidal anti-inflammatory drugs (NSAIDs). The prepared materials were characterized by different analytical methods such as transmission electron microscopy (TEM), infrared spectroscopy (IR), nitrogen adsorption/desorption analysis (N2), thermogravimetric analysis (TG), 1H, 13C and 23Na solid-state nuclear magnetic resonance spectroscopy (1H, 13C and 23Na ss-NMR). The abovementioned analytical techniques confirmed the successful grafting of functional groups to the SBA-15 surface and the adsorption of drugs after the impregnation process. The BET area values decreased from 927 m2 g-1 for SBA-15 to 408 m2 g-1 for SBA-15-NCO. After drug encapsulation, a more significant decrease in surface area was observed due to the filling of pores with drug molecules, while the most significant decrease was observed for the SBA-15-NH2 material (115 m2 g-1 for NaNAP and 101 m2 g-1 for HNAP). By combining TG and nitrogen adsorption results, the occurrence of functional groups and the affinity of drugs to the carriers' surface were calculated. The dominant factor was the volume of functional groups and intermolecular interactions. The highest drug affinity values were observed for phenyl and amine-modified materials (SBA-15-Ph = 1.379 µmol m-2 mmol-1 for NaNAP, 1.761 µmol m-2 mmol-1 for HNAP and SBA-15-NH2 = 1.343 µmol m-2 mmol-1 for NaNAP, 1.302 µmol m-2 mmol-1 for HNAP) due to the formation of hydrogen bonds and π-π interactions, respectively. Drug release properties and kinetic studies were performed at t = 37 °C (normal human body temperature) in different media with pH = 2 as simulated human gastric fluid and pH = 7.4, which simulated a physiological environment. Determination of drug release quantity was performed with UV-VIS spectroscopy. The surface polarity, pH and naproxen form influenced the total released amount of drug. In general, naproxen sodium salt has a higher solubility than its acid form, thus significantly affecting drug release from surface-modified SBA-15 materials. Different pH conditions involved surface protonation and formation/disruption of intermolecular interactions, influencing both the release rate and the total released amount of naproxen. Different kinetic models, zero-order, first-order, Higuchi and Hixson-Crowell models, were used to fit the drug release data. According to the obtained experimental results, the drug release rates and mechanisms were determined.

A Cost Effective Scheme for the Highly Accurate Description of Intermolecular Binding in Large Complexes.

There has been a growing interest in quantitative predictions of the intermolecular binding energy of large complexes. One of the most important quantum chemical techniques capable of such predictions is the domain-based local pair natural orbital (DLPNO) scheme for the coupled cluster theory with singles, doubles, and iterative triples [CCSD(T)], whose results are extrapolated to the complete basis set (CBS) limit. Here, the DLPNO-based focal-point method is devised with the aim of obtaining CBS-extrapolated values that are very close to their canonical CCSD(T)/CBS counterparts, and thus may serve for routinely checking a performance of less expensive computational methods, for example, those based on the density-functional theory (DFT). The efficacy of this method is demonstrated for several sets of noncovalent complexes with varying amounts of the electrostatics, induction, and dispersion contributions to binding (as revealed by accurate DFT-based symmetry-adapted perturbation theory (SAPT) calculations). It is shown that when applied to dimeric models of poly(3-hydroxybutyrate) chains in its two polymorphic forms, the DLPNO-CCSD(T) and DFT-SAPT computational schemes agree to within about 2 kJ/mol of an absolute value of the interaction energy. These computational schemes thus should be useful for a reliable description of factors leading to the enthalpic stabilization of extended systems.

Anisotropy, segmental dynamics and polymorphism of crystalline biogenic carboxylic acids.

Carboxylic acids of the Krebs cycle possess invaluable biochemical significance. Still, there are severe gaps in the availability of thermodynamic and crystallographic data, as well as ambiguities prevailing in the literature on the thermodynamic characterization and polymorph ranking. Providing an unambiguous description of the structure, thermodynamics and polymorphism of their neat crystalline phases requires a complex multidisciplinary approach. This work presents results of an extensive investigation of the structural anisotropy of the thermal expansion and local dynamics within these crystals, obtained from a beneficial cooperation of NMR crystallography and ab initio calculations of non-covalent interactions. The observed structural anisotropy and spin-lattice relaxation times are traced to large spatial variations in the strength of molecular interactions in the crystal lattice, especially in the orientation of the hydrogen bonds. A completely resolved crystal structure for oxaloacetic acid is reported for the first time. Thanks to multi-instrumental calorimetric effort, this work clarifies phase behavior, determines third-law entropies of the crystals, and states definitive polymorph ranking for succinic and fumaric acids. These thermodynamic observations are then interpreted in terms of first-principles quasi-harmonic calculations of cohesive properties. A sophisticated model capturing electronic, thermal, and configurational-entropic effects on the crystal structure approaches captures the subtle Gibbs energy differences governing polymorph ranking for succinic and fumaric acids, representing another success story of computational chemistry.

Rational Design of Self-Emulsifying Pellet Formulation of Thymol: Technology Development Guided by Molecular-Level Structure Characterization and Ex Vivo Testing.

The growing need for processing natural lipophilic and often volatile substances such as thymol, a promising candidate for topical treatment of intestinal mucosa, led us to the utilization of solid-state nuclear magnetic resonance (ss-NMR) spectroscopy for the rational design of enteric pellets with a thymol self-emulsifying system (SES). The SES (triacylglycerol, Labrasol®, and propylene glycol) provided a stable o/w emulsion with particle size between 1 and 7 µm. The ex vivo experiment confirmed the SES mucosal permeation and thymol delivery to enterocytes. Pellets W90 (MCC, Neusilin®US2, chitosan) were prepared using distilled water (90 g) by the M1−M3 extrusion/spheronisation methods varying in steps number and/or cumulative time. The pellets (705−740 µm) showed mostly comparable properties­zero friability, low intraparticular porosity (0−0.71%), and relatively high density (1.43−1.45%). They exhibited similar thymol release for 6 h (burst effect in 15th min ca. 60%), but its content increased (30−39.6 mg/g) with a shorter process time. The M3-W90 fluid-bed coated pellets (Eudragit®L) prevented undesirable thymol release in stomach conditions (<10% for 3 h). A detailed, ss-NMR investigation revealed structural differences across samples prepared by M1−M3 methods concerning system stability and internal interactions. The suggested formulation and methodology are promising for other lipophilic volatiles in treating intestinal diseases.

Ion-modulated radical doping of spiro-OMeTAD for more efficient and stable perovskite solar cells.

Record power conversion efficiencies (PCEs) of perovskite solar cells (PSCs) have been obtained with the organic hole transporter 2,2',7,7'-tetrakis(N,N-di-p-methoxyphenyl-amine)9,9'-spirobifluorene (spiro-OMeTAD). Conventional doping of spiro-OMeTAD with hygroscopic lithium salts and volatile 4-tert-butylpyridine is a time-consuming process and also leads to poor device stability. We developed a new doping strategy for spiro-OMeTAD that avoids post-oxidation by using stable organic radicals as the dopant and ionic salts as the doping modulator (referred to as ion-modulated radical doping). We achieved PCEs of >25% and much-improved device stability under harsh conditions. The radicals provide hole polarons that instantly increase the conductivity and work function (WF), and ionic salts further modulate the WF by affecting the energetics of the hole polarons. This organic semiconductor doping strategy, which decouples conductivity and WF tunability, could inspire further optimization in other optoelectronic devices.

A computational inspection of the dissociation energy of mid-sized organic dimers.

The gas-phase value of the dissociation energy (D0) is a key parameter employed in both experimental and theoretical descriptions of noncovalent complexes. The D0 data were obtained for a set of mid-sized organic dimers in their global minima which was located using geometry optimizations that applied ample basis sets together with either the conventional second-order Møller-Plesset (MP2) method or several dispersion-corrected density-functional theory (DFT-D) schemes. The harmonic vibrational zero-point (VZP) and deformation energies from the MP2 calculations were combined with electronic energies from the coupled cluster theory with singles, doubles, and iterative triples [CCSD(T)] extrapolated to the complete basis set (CBS) limit to estimate D0 with the aim of inspecting values that were most recently measured, and an analogous comparison was performed using the DFT-D data. In at least one case (namely, for the aniline⋯methane cluster), the D0 estimate that employed the CCSD(T)/CBS energies differed from experiment in the way that could not be explained by a possible deficiency in the VZP contribution. Curiously, one of the DFT-D schemes (namely, the B3LYP-D3/def2-QZVPPD) was able to reproduce all measured D0 values to within 1.0 kJ/mol from experimental error bars. These findings show the need for further measurements and computations of some of the complexes. In order to facilitate such studies, the physical nature of intermolecular interactions in the investigated dimers was analyzed by means of the DFT-based symmetry-adapted perturbation theory.

Fluorinated diselenide nanoparticles for radiosensitizing therapy of cancer.

Radiation resistance of cancer cells represents one of the major challenges in cancer treatment. The novel self-assembled fluoralkylated diselenide nanoparticles (fluorosomes) based on seleno-l-cystine (17FSe2) possess redox-active properties that autocatalytically decompose hydrogen peroxide (H2O2) and oxidize the intracellular glutathione (GSH) that results in regulation of cellular oxidative stress. Alkylfluorinated diselenide nanoparticles showed a significant cytotoxic and radiosensitizing effect on cancer cells. The EL-4 tumor-bearing C56BL/6 mice treated with 17FSe2 followed by fractionated radiation treatment (4 × 2Gy) completely suppressed tumor growth. Our results suggest that described diselenide system behaves as a potent radiosensitizer agent targeting tumor growth and preventing tumor recurrence.

Formation and local structure of framework Al Lewis sites in beta zeolites.

Framework AlFR Lewis sites represent a substantial portion of active sites in H-BEA zeolite catalysts activated at low temperatures. We studied their nature by 27Al WURST-QCPMG nuclear magnetic resonance (NMR) and proposed a plausible mechanism of their formation based on periodic density functional theory calculations constrained by 1H MAS, 27Al WURST-QCPMG, and 29Si MAS NMR experiments and FTIR measurements. Our results show that the electron-pair acceptor of AlFR Lewis sites corresponds to an AlTRI atom tricoordinated to the zeolite framework, which adsorbs a water molecule. This AlTRI-OH2 complex is reflected in 27Al NMR resonance with δiso = 70 ± 5 ppm and CQ = 13 ± 2 MHz. In addition, the AlTRI atom with adsorbed acetonitrile-d3 (the probe of AlFR Lewis sites in FTIR spectroscopy) exhibits a similar 27Al NMR resonance. We suggest that these AlFR Lewis sites are formed from Al-OH-Si-O-Si-O-Si-OH-Al sequences located in 12-rings (i.e., close unpaired Al atoms).

Enantiotropy of Simvastatin as a Result of Weakened Interactions in the Crystal Lattice: Entropy-Driven Double Transitions and the Transient Modulated Phase as Seen by Solid-State NMR Spectroscopy.

In crystalline molecular solids, in the absence of strong intermolecular interactions, entropy-driven processes play a key role in the formation of dynamically modulated transient phases. Specifically, in crystalline simvastatin, the observed fully reversible enantiotropic behavior is associated with multiple order-disorder transitions: upon cooling, the dynamically disordered high-temperature polymorphic Form I is transformed to the completely ordered low-temperature polymorphic Form III via the intermediate (transient) modulated phase II. This behavior is associated with a significant reduction in the kinetic energy of the rotating and flipping ester substituents, as well as a decrease in structural ordering into two distinct positions. In transient phase II, the conventional three-dimensional structure is modulated by periodic distortions caused by cooperative conformation exchange of the ester substituent between the two states, which is enabled by weakened hydrogen bonding. Based on solid-state NMR data analysis, the mechanism of the enantiotropic phase transition and the presence of the transient modulated phase are documented.

Modeling the Structure of Crystalline Alamethicin and Its NMR Chemical Shift Tensors.

Alamethicin (ALM) is an antimicrobial peptide that is frequently employed in studies of the mechanism of action of pore-forming molecules. Advanced techniques of solid-state NMR spectroscopy (SSNMR) are important in these studies, as they are capable of describing the alignment of helical peptides, such as ALM, in lipid bilayers. Here, it is demonstrated how an analysis of the SSNMR measurements can benefit from fully periodic calculations, which employ the plane-wave density-functional theory (PW DFT) of the solid-phase geometry and related spectral parameters of ALM. The PW DFT calculations are used to obtain the structure of desolvated crystalline ALM and predict the NMR chemical shift tensors (CSTs) of its nuclei. A variation in the CSTs of the amidic nitrogens and carbonyl carbons along the ALM backbone is evaluated and included in simulations of the orientation-dependent anisotropic 15N and 13C chemical shift components. In this way, the influence of the site-specific structural effects on the experimentally determined orientation of ALM is shown in models of cell membranes.

Reconstructing Reliable Powder Patterns from Spikelets (Q)CPMG NMR Spectra: Simplification of UWNMR Crystallography Analysis.

Spikelets NMR spectra are very popular as they enable the shortening of experimental time and give the possibility to obtain required NMR parameters for nuclei with ultrawide NMR patterns. Unfortunately, these resulted ssNMR spectra cannot be fitted directly in common software. For this reason, we developed UWNMRSpectralShape (USS) software which transforms spikelets NMR patterns into single continuous lines. Subsequently, these reconstructed spectral envelopes of the (Q)CPMG spikelets patterns can be loaded into common NMR software and automatically fitted, independently of experimental settings. This allows the quadrupole and chemical shift parameters to be accurately determined. Moreover, it makes fitting of spikelets NMR spectra exact, fast and straightforward.