Baltzar Stevensson

On the Treatment of Conformational Flexibility when Using Residual Dipolar Couplings for Structure Determination

Mission possible! The motional averaging of NMR spectroscopic data complicates the determination of conformation and relative configuration in flexible organic molecules. Two alternative routes are discussed for the treatment of conformational equilibrium in a moderately flexible compound (see the superposition of the two conformers of the butyrolactone studied) when residual dipolar couplings are used.

Computer-intensive simulation of solid-state NMR experiments using SIMPSON.

Conducting large-scale solid-state NMR simulations requires fast computer software potentially in combination with efficient computational resources to complete within a reasonable time frame. Such simulations may involve large spin systems, multiple-parameter fitting of experimental spectra, or multiple-pulse experiment design using parameter scan, non-linear optimization, or optimal control procedures. To efficiently accommodate such simulations, we here present an improved version of the widely distributed open-source SIMPSON NMR simulation software package adapted to contemporary high performance hardware setups. The software is optimized for fast performance on standard stand-alone computers, multi-core processors, and large clusters of identical nodes. We describe the novel features for fast computation including internal matrix manipulations, propagator setups and acquisition strategies. For efficient calculation of powder averages, we implemented interpolation method of Alderman, Solum, and Grant, as well as recently introduced fast Wigner transform interpolation technique. The potential of the optimal control toolbox is greatly enhanced by higher precision gradients in combination with the efficient optimization algorithm known as limited memory Broyden-Fletcher-Goldfarb-Shanno. In addition, advanced parallelization can be used in all types of calculations, providing significant time reductions. SIMPSON is thus reflecting current knowledge in the field of numerical simulations of solid-state NMR experiments. The efficiency and novel features are demonstrated on the representative simulations.

Local structures and Al/Si ordering in lanthanum aluminosilicate glasses explored by advanced 27Al NMR experiments and molecular dynamics simulations

The structures of 15 La-Al-Si-O glasses, whose compositions span 11-28 mol% La(2)O(3), 11-30 mol% Al(2)O(3), and 45-78 mol% SiO(2), are explored over both short and intermediate length-scales by using a combination of solid-state (27)Al magic-angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics (MD) simulations. MAS NMR reveals Al speciations dominated by AlO(4) groups, with minor but significant fractions of AlO(5) (5-10%) and AlO(6) (≲3%) polyhedra present in all La(2)O(3)-Al(2)O(3)-SiO(2) glasses; the amounts of Al([5]) and Al([6]) coordinations increase for decreasing molar fraction of Si. The MD simulations reproduce this compositional trend, with the fractional populations of AlO(p) groups (p = 4, 5, 6) according well with the experimental results. The modeled La speciations mainly involve LaO(6) and LaO(7) polyhedra, giving a range of average La(3+) coordination numbers between 6.0 and 6.6; the latter increases slightly for decreasing Si content of the sample. Besides the expected bridging and non-bridging O species, minor contributions of oxygen triclusters (≤9%) and free O(2-) ions (≤4%) are observed in all MD data. The glass structures exhibit a pronounced Al/Si disorder; the MD simulations reveal essentially random SiO(4)-SiO(4), SiO(4)-AlO(p) and AlO(p)-AlO(q) (p, q = 4, 5, 6) associations, including significant amounts of AlO(4)-AlO(4) contacts, regardless of the n(Al)/n(Si) molar ratio of the glass. The strong violation of Al([4])-Al([4]) avoidance is verified by 2D (27)Al NMR experimentation that correlates double-quantum and single-quantum coherences, here applied for the first time to aluminosilicate glasses, and evidencing AlO(p)-AlO(q) connectivities dominated by AlO(4)-AlO(4) and AlO(4)-AlO(5) pairs. The potential bearings from distinct fictive temperatures of the experimental and modeled glass structures are discussed.

NMR investigations of interactions between anesthetics and lipid bilayers

Interactions between anesthetics (lidocaine and short chain alcohols) and lipid membranes formed by dimyristoylphosphatidylcholine (DMPC) were studied using NMR spectroscopy. The orientational order of lidocaine was investigated using deuterium NMR on a selectively labelled compound whereas segmental ordering in the lipids was probed by two-dimensional 1H-13C separated local field experiments under magic-angle spinning conditions. In addition, trajectories generated in molecular dynamics (MD) computer simulations were used for interpretation of the experimental results. Separate simulations were carried out with charged and uncharged lidocaine molecules. Reasonable agreement between experimental dipolar interactions and the calculated counterparts was observed. Our results clearly show that charged lidocaine affects significantly the lipid headgroup. In particular the ordering of the lipids is increased accompanied by drastic changes in the orientation of the P-N vector in the choline group.

Molecular dynamics simulations of membrane-sugar interactions.

It is well documented that disaccharides in general and trehalose (TRH) in particular strongly affect physical properties and functionality of lipid bilayers. We investigate interactions between lipid membranes formed by 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and TRH by means of molecular dynamics (MD) computer simulations. Ten different TRH concentrations were studied in the range wTRH = 0-0.20 (w/w). The potential of mean force (PMF) for DMPC bilayer-TRH interactions was determined using two different force fields, and was subsequently used in a simple analytical model for description of sugar binding at the membrane interface. The MD results were in good agreement with the predictions of the model. The net affinities of TRH for the DMPC bilayer derived from the model and MD simulations were compared with experimental results. The area per lipid increases and the membrane becomes thinner with increased TRH concentration, which is interpreted as an intercalation effect of the TRH molecules into the polar part of the lipids, resulting in conformational changes in the chains. These results are consistent with recent experimental observations. The compressibility modulus related to the fluctuations of the membrane increases dramatically with increased TRH concentration, which indicates higher order and rigidity of the bilayer. This is also reflected in a decrease (by a factor of 15) of the lateral diffusion of the lipids. We interpret these observations as a formation of a glassy state at the interface of the membrane, which has been suggested in the literature as a hypothesis for the membrane-sugar interactions.

Conformational distribution functions extracted from residual dipolar couplings: A hybrid model based on maximum entropy and molecular field theory

This paper describes a new approach for analysis of residual dipolar couplings (RDCs). The method, which focuses on construction of the conformational distribution function, is applied to 4-n-pentyl-4′-cyanobiphenyl in the nematic phase. The RDCs are calculated from a trajectory generated in a molecular dynamics (MD) simulation, based on a realistic atom–atom interaction potential. Computer simulation is an attractive method for investigating theoretical models for partially ordered systems since the answer is provided: we know the true orientational order and molecular structure. Our new approach is based on two models that have been frequently used for interpretations of dipolar couplings in liquid crystals: the additive potential (AP) model and the maximum entropy (ME) method. These models suffer, however, from serious limitations: the AP model requires a priori knowledge of the functional form of the torsional potential, whereas the ME approach gives the flattest possible distribution, which results i...

Molecular Dynamics Simulations of Membranes Composed of Glycolipids and Phospholipids

Lipid membranes composed of 1,2-di-(9Z,12Z,15Z)-octadecatrienoyl-3-O-β-D-galactosyl-sn-glycerol or monogalactosyldiacylglycerol (MGDG) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) were studied by means of molecular dynamics (MD) computer simulations. Three lipid compositions were considered: 0%, 20%, and 45% MGDG (by mole) denoted as MG-0, MG-20, and MG-45, respectively. The article is focused on the calculation of NMR dipolar interactions, which were confronted with previously reported experimental couplings. Dynamical processes and orientational distributions relevant for the averaging of dipolar interactions were evaluated. Furthermore, several parameters important for characterization of the bilayer structure, molecular organization, and dynamics were investigated. In general, only a minor change in DMPC properties was observed upon the increased MGDG/DMPC ratio, whereas properties related to MGDG undergo a more pronounced change. This effect was ascribed to the fact that DMPC is a bilayer (L(α)) forming lipid, whereas MGDG prefers a reverse hexagonal (H(II)) arrangement.

Structure and molecular ordering extracted from residual dipolar couplings: A molecular dynamics simulation study

A molecular dynamics (MD) simulation, based on a realistic atom–atom interaction potential, was performed on 4-n-pentyl-4′-cyanobiphenyl (5CB) in the nematic phase. The analysis of the trajectory was focused on the determination of molecular structure and orientational ordering using nuclear dipole–dipole couplings. Three sets of couplings were calculated: 13C–13C, 13C–1H, and 1H–1H. These dipolar couplings were used for investigation of the biphenyl and the ring–chain fragments in 5CB. The models employed in the analysis were based on the rotational isomeric state (RIS) approximation and the maximum entropy (ME) approach. The main questions addressed in this article are: (i) How sensitive are the various sets of dipolar couplings to the long-range orientational order and molecular conformation? (ii) Which model predicts a molecular structure that is in best agreement with the true conformation? Computer simulation is an attractive method to address these questions since the answer is provided: we know th...

Toward a Rational Design of Bioactive Glasses with Optimal Structural Features: Composition–Structure Correlations Unveiled by Solid-State NMR and MD Simulations

The physiological responses of silicate-based bioactive glasses (BGs) are known to depend critically on both the P content (nP) of the glass and its silicate network connectivity (N̅BOSi). However, while the bioactivity generally displays a nonmonotonic dependence on nP itself, recent work suggest that it is merely the net orthophosphate content that directly links to the bioactivity. We exploit molecular dynamics (MD) simulations combined with 31P and 29Si solid-state nuclear magnetic resonance (NMR) spectroscopy to explore the quantitative relationships between N̅BOSi, nP, and the silicate and phosphate speciations in a series of Na2O–CaO–SiO2–P2O5 glasses spanning 2.1 ≤ N̅BOSi ≤ 2.9 and variable P2O5 contents up to 6.0 mol %. The fractional population of the orthophosphate groups remains independent of nP at a fixed N̅BOSi-value, but is reduced slightly as N̅BOSi increases. Nevertheless, P remains predominantly as readily released orthophosphate ions, whose content may be altered essentially independently of the network connectivity, thereby offering a route to optimize the glass bioactivity. We discuss the observed composition-structure links in relation to known composition-bioactivity correlations, and define how Na2O–CaO–SiO2–P2O5 compositions exhibiting an optimal bioactivity can be designed by simultaneously altering three key parameters: the silicate network connectivity, the (ortho)phosphate content, and the nNa/nCa molar ratio.

Composition-dependent in vitro apatite formation at mesoporous bioactive glass-surfaces quantified by solid-state NMR and powder XRD

Silicate-based bioactive glasses exhibit bone-bonding properties due to the formation of a hydroxy-carbonate apatite (HCA) layer at the glass surface on its contact with living tissues. This bone-healing process is triggered by ionic exchange between the glass and the surrounding fluids and thereby depends on the glass composition. In this work, the HCA formation from three mesoporous bioactive glasses (MBGs) of different compositions immersed in a simulated body fluid (SBF) was monitored for variable time intervals between 15 minutes to 30 days. By utilizing two independent assessment techniques, solid-state 31P NMR spectroscopy and powder X-ray diffraction (PXRD), we report the first quantitative assessment of the HCA growth (i.e., “in vitro bioactivity”) from a bioactive glass: both techniques allow for monitoring the crystallization of the amorphous calcium phosphate (ACP) precursor into HCA, i.e., a profile of the relative ACP/HCA fractions of the biomimetic phosphate layer formed at each MBG surface and SBF-exposure period. The amount of HCA present in each solid specimen after the SBF treatment, as well as the composition of the remaining cation-depleted MBG phase, was determined from PXRD data in conjunction with measured concentrations of Ca, Si, and P in the solution. In contrast with previous findings from in vitro bioactivity assessments of the same MBG compositions, the HCA formation is herein observed to increase concurrently with the Ca and P contents of the MBG; these apparently different composition-bioactivity observations stem from a significantly lower MBG-loading in the SBF solution utilized herein. The results are discussed in relation to the general task of performing bioactivity testing in SBF, where we highlight the importance of adapting the concentration of the biomaterial to its composition to avoid perturbing the HCA crystallization and thereby altering the outcome of the test.