Unveiling the conformational landscape of achiral all-cis tert-butyl ß-peptoids.

The synthesis and conformational study of N-substituted ß-alanines with tert-butyl side chains is described. The oligomers prepared by submonomer synthesis and block coupling methods are up to 15 residues long and are characterised by amide bonds in the cis-conformation. A conformational study comprising experimental solution NMR spectroscopy, X-ray crystallography and molecular modeling shows that despite their intrinsic higher conformational flexibility compared to their α-peptoid counterparts, this family of achiral oligomers adopt preferred secondary structures including a helical conformation close to that described with (1-naphthyl)ethyl side chains but also a novel ribbon-like conformation.

Evidence for amylose inclusion complexes with multiple acyl chain lipids using solid-state NMR and theoretical approaches.

Amylose is known to form inclusion complexes in the presence of hydrophobic guests. Among lipids, only single-chain fatty acids have been reported as possible guests with the surrounding amylose in a well-defined V-helix conformation. Using experimental 13C solid-state NMR, we studied the formation of inclusion complexes between amylose and a variety of multiple-chains lipids of increasing complexity. Molecular dynamics simulations and calculations of 13C isotropic chemical shifts using the Density Functional Theory approach were performed to support the interpretation of experimental spectra. We provide unambiguous evidences that amylose forms inclusion complexes with lipids bearing multiple acyl chains. Amylose conformations around these lipids are characterized by {ϕ,ψ} anomeric bond dihedral angles near {115°,105°}. In the 13C NMR spectra, this translates into C1 and C4 chemical shifts of 102.5 ppm and 81.1 ppm, regardless of the helical conformation of the amylose surrounding the acyl chains.

Nanocatalysts for High Selectivity Enyne Cyclization: Oxidative Surface Reorganization of Gold Sub-2-nm Nanoparticle Networks.

Ultrasmall gold nanoparticles (NPs) stabilized in networks by polymantane ligands (diamondoids) were successfully used as precatalysts for highly selective heterogeneous gold-catalyzed dimethyl allyl(propargyl)malonate cyclization to 5-membered conjugated diene. Such reaction usually suffers from selectivity issues with homogeneous catalysts. This control over selectivity further opened the way to one-pot cascade reaction, as illustrated by the 1,6-enyne cycloisomerization-Diels-Alder reaction of dimethyl allyl propargyl malonate with maleic anhydride. The ability to assemble nanoparticles with controllable sizes and shapes within networks concerns research in sensors, medical diagnostics, information storage, and catalysis applications. Herein, the control of the synthesis of sub-2-nm gold NPs is achieved by the formation of dense networks, which are assembled in a single step reaction by employing ditopic polymantanethiols. By using 1,1'-bisadamantane-3,3'-dithiol (BAd-SH) and diamantane-4,9-dithiol (DAd-SH), serving both as bulky surface stabilizers and short-sized linkers, we provide a simple method to form uniformly small gold NPs (1.3 ± 0.2 nm to 1.6 ± 0.3 nm) embedded in rigid frameworks. These NP arrays are organized alongside short interparticular distances ranging from 1.9 to 2.7 nm. The analysis of gold NP surfaces and their modification were achieved in joint experimental and theoretical studies, using notably XPS, NMR, and DFT modeling. Our experimental studies and DFT analyses highlighted the necessary oxidative surface reorganization of individual nanoparticles for an effective enyne cycloisomerization. The modifications at bulky stabilizing ligands allow surface steric decongestion for the alkyne moiety activation but also result in network alteration by overoxidation of sulfurs. Thus, sub-2-nm nanoparticles originating from networks building create convenient conditions for generating reactive Au(I) surface single-sites-in the absence of silver additives-useful for heterogeneous gold-catalyzed enyne cyclization. These nanocatalysts, which as such ease organic products separation, also provide a convenient access for building further polycyclic complexity, owing to their high reactivity and selectivity.

Diversity of the Hydrogen Bond Network and Its Impact on NMR Parameters of Amylose B Polymorph: A Study Using Molecular Dynamics and DFT Calculations Within Periodic Boundary Conditions.

Classical molecular dynamics simulations have been combined with quantum (DFT) calculations of 13C NMR parameters in order to relate the experimental spectrum of the double-helix form of the amylose B-polymorph in highly crystalline conditions not only to its 3D structure but also to the arrangement of atoms in the crystal lattice. Structures obtained from these simulations or from geometry optimization procedures at the DFT level have shown the presence of hydrogen bond networks between sugars of the same helix or between residues of the two chains of the double helix. 13C NMR parameter calculations have revealed the impact of such a network on the chemical shifts of carbon atoms. In addition, DFT calculations using periodic boundary conditions were compulsory to highlight the presence of two types of sugar within the crystal sample. It allows us to confirm, theoretically, the experimental hypothesis that the existence of two distinct sugar types in the NMR spectrum is a consequence of crystal packing.

Molecular nature of breakdown of the folic acid under hydrothermal treatment: a combined experimental and DFT study.

Using a combination of experimental Raman, FTIR, UV-VIS absorption and emission data, together with the corresponding DFT calculations we propose the mechanism of modification of the folic acid specifically under the hydrothermal treatment at 200 °C. We established that folic acid breaks down into fragments while the pteridine moiety remains intact likely evolving into 6-formylpterin with the latter responsible for the increase in fluorescence emission at 450 nm. The results suggest that hydrothermal approach can be used for production of other purpose-engineered fluorophores.

Relating circular dichroism to atomic structure by means of MD simulations and computed CD spectra with α-peptoids as an example.

Classical molecular dynamics simulations have been combined with quantum calculations of CD spectra in order to fruitfully relate the experimental CD spectra, not only to the overall conformation of chiral α-peptoids, but also to their structure at the atomic scale, including the dihedral feature of the backbone (ψ,φ) and the orientation of the chiral side-chain (χ1). These simulations have been performed up to the hexamer Ac-(stbe)6-CO2tBu. We have shown that the number of states has a significant impact on the shape of the spectrum below 215 nm. The number of states computed is also critical to simulate the spectra of long oligomers. While 10 to 20 states are sufficient to simulate the CD spectra of short oligomers, 100 states or more are mandatory to converge the CD spectral shape for longer oligomers. The conformational sampling and the analysis of the intramolecular interactions responsible for the specific folding of the objects have been jointly explored by means of Replica Exchange MD and DFT calculations.

Structures and NMR spectra of short amylose-lipid complexes. Insight using molecular dynamics and DFT quantum chemical calculations.

It is well established that amylose folds in a helix conformation in presence of lipids. Structural features of such molecular complexes are often analysed using 13C NMR spectroscopy. The large size of amylose used to make such analysis doesn't allow to unambiguously correlate structure of polymers and spectroscopic signals. We present structural analysis of small sized amyloses complexed to palmitic acid using classical molecular dynamics. 15 glucoses residues are necessary for the amylose to fold around the palmitic acid in a well-established helix conformation. Simulating 13C NMR spectra using quantum chemical DFT approach, we demonstrate that these spectra are affected by amylose size and specific intramolecular hydrogen bonds. By mean of theoretical NMR spectra of a 19-residues amylose, we precise the attribution of each characteristic resonances. One chemical shift that is usually attributed to a specific carbon may be related to the existence of different inter or intramolecular hydrogen bonds.

The conical shape of DIM lipids promotes Mycobacterium tuberculosis infection of macrophages.

Phthiocerol dimycocerosate (DIM) is a major virulence factor of the pathogen Mycobacterium tuberculosis (Mtb). While this lipid promotes the entry of Mtb into macrophages, which occurs via phagocytosis, its molecular mechanism of action is unknown. Here, we combined biophysical, cell biology, and modeling approaches to reveal the molecular mechanism of DIM action on macrophage membranes leading to the first step of Mtb infection. Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry showed that DIM molecules are transferred from the Mtb envelope to macrophage membranes during infection. Multiscale molecular modeling and 31P-NMR experiments revealed that DIM adopts a conical shape in membranes and aggregates in the stalks formed between 2 opposing lipid bilayers. Infection of macrophages pretreated with lipids of various shapes uncovered a general role for conical lipids in promoting phagocytosis. Taken together, these results reveal how the molecular shape of a mycobacterial lipid can modulate the biological response of macrophages.

Evaluation of Gas-to-Liquid 17O Chemical Shift of Water: A Test Case for Molecular and Periodic Approaches.

Modeling liquid water features is a challenging and ongoing task that brings together a number of computational issues related to the description both of its electronic and geometrical structure. In order to go a step further in the understanding of this peculiar liquid, we present a thorough analysis of NMR gas-to-liquid 17O and 1H shifts of water using density functional theory based molecular dynamics. In order to be as consistent as possible, we consider the influence of basis sets, exchange-correlation functionals, and structural models, in both molecular and periodic schemes, to evaluate 17O and 1H nuclear shieldings. We show that strong error compensations between functional and basis-set expansion can be obtained in molecular approaches which artificially produces good 17O gas-to-liquid shifts with relatively small basis sets. We also demonstrate that, despite their ability to provide reliable liquid phase structures, generalized-gradient approximation based exchange-correlation functionals lead to strongly inconsistent values for 17O gas-to-liquid shift. This latter property is shown to be strongly influenced by intramolecular electronic delocalization, accentuated by the surrounded molecules. In contrast, 1H is less sensitive to this effect. By including a Hartree-Fock exchange term, through the use of hybrid functionals which partially correct the self-interaction error, better agreement with experimental values is obtained. The present study provides a detailed guideline to properly evaluate gas-to-liquid shifts in hydrogen bonded systems and emphasizes that, for nuclear shieldings, an accurate electronic structure evaluation prevails over the description of the liquid structure.

Exploring the Conformation of Mixed Cis- Trans α,ß-Oligopeptoids: A Joint Experimental and Computational Study.

The synthesis and conformational preferences of a set of new synthetic foldamers that combine both the α,ß-peptoid backbone and side chains that alternately promote cis- and trans-amide bond geometries have been achieved and addressed jointly by experiment and molecular modeling. Four sequence patterns were thus designed and referred to as cis-ß- trans-α, cis-α- trans-ß, trans-ß- cis-α, and trans-α- cis-ß. α- and ß NtBu monomers were used to enforce cis-amide bond geometries and α- and ß NPh monomers to promote trans-amides. NOESY and molecular modeling reveal that the trans-α- cis-ß and cis-ß- trans-α tetramers show a similar pattern of intramolecular weak interactions. The same holds for the cis-α- trans-ß and trans-ß- cis-α tetramers, but the interactions are different in nature than those identified in the trans-α- cis-ß-based oligomers. Interestingly, the trans-α- cis-ß peptoid architecture allows establishment of a larger amount of structure-stabilizing intramolecular interactions.

Prediction of pKa Using DFT: the Nicotianamine Polyacid Example.

The determination of pKa values for molecules containing multiple acidic groups in solution is challenging both experimentally and theoretically. We propose a general method to obtain these values by combining a graphical analysis based on a predominance diagram, for amino acids and nicotianamine polyacid, with first principle DFT calculations. Implicit and semiexplicit water solvent models were included to account for solvation. This strategy enables the investigation of the protonation states of compounds containing acidic moieties in solution depending on the pH domain. The method was first validated on a set of amino acids with pKa values calculated with an accuracy within 0.5-1.0 pKa unit and then on the chalenging nicotianamine polyacid with six pKa values. This approach is particularly well suited for such a complex system including both zwitterionic structures and unknown experimental pKa values.

Theoretical gas to liquid shift of (15)N isotropic nuclear magnetic shielding in nitromethane using ab initio molecular dynamics and GIAO/GIPAW calculations.

Chemical shift requires the knowledge of both the sample and a reference magnetic shielding. In few cases as nitrogen (15N), the standard experimental reference corresponds to its liquid phase. Theoretical estimate of NMR magnetic shielding parameters of compounds in their liquid phase is then mandatory but usually replaced by an easily-get gas phase value, forbidding direct comparisons with experiments. We propose here to combine ab initio molecular dynamic simulations with the calculations of magnetic shielding using GIAO approach on extracted cluster's structures from MD. Using several computational strategies, we manage to accurately calculate 15N magnetic shielding of nitromethane in its liquid phase. Theoretical comparison between liquid and gas phase allows us to extrapolate an experimental value for the 15N magnetic shielding of nitromethane in gas phase between -121.8 and -120.8 ppm.

Hydrogen bonding of cholesterol in the lipidic cubic phase.

The addition of cholesterol to the monoolein-based lipidic cubic phase (LCP) has been instrumental in obtaining high-resolution crystal structures of several G protein-coupled receptors. Here, we report the use of high-resolution magic angle spinning NMR spectroscopy to record and assign the isotropic (13)C chemical shifts of cholesterol in lipidic lamellar and cubic phases at different hydration levels with monoolein and chain-deuterated DMPC as host lipids. The hydrogen-bonding patterns of cholesterol in these phases were determined from the NMR data by quantum chemical calculations. The results are consistent with the normal orientation of cholesterol in lipid bilayers and with the cholesterol hydroxyl group located at the hydrophobic/hydrophilic interface. The (13)C chemical shifts of cholesterol are mostly affected by the host lipid identity with little or no dependency on the hydration (20% vs 40%) or the phase identity (lamellar vs LCP). In chain-deuterated DMPC bilayers, the hydroxyl group of cholesterol forms most of its hydrogen bonds with water, while in monoolein bilayers it predominately interacts with monoolein. Such differences in the hydrogen-bonding network of cholesterol may have implications for the design of experiments in monoolein-based LCP.

Theoretical and experimental studies on the carbon-nanotube surface oxidation by nitric acid: interplay between functionalization and vacancy enlargement.

The nitric acid oxidation of multiwalled carbon nanotubes leading to surface carboxylic groups has been investigated both experimentally and theoretically. The experimental results show that such a reaction involves the initial rapid formation of carbonyl groups, which are then transformed into phenol or carboxylic groups. At room temperature, this reaction takes place on the most reactive carbon atoms. At higher temperatures a different mechanism would operate, as evidenced by the difference in activation energies. Experimental data can be partially related to first-principles calculations, showing a multistep functionalization mechanism. The theoretical aspects of the present article have led us to propose the most efficient pathway leading to carboxylic acid functional groups on the surface. Starting from mono-vacancies, it ends up with the synergistic formation of dangling -COOH groups and the enlargement of the vacancies.

Ab initio molecular dynamics studies of tetrasulfur. Dynamics coupling the C2v open and D2h closed forms of S4.

Ab initio molecular dynamics (AIMD) simulations were performed on the closed D(2h) and open C(2v) isomers of tetrasulfur. After a careful calibration of the electronic structure method, the calculations were done using the BPW91/aug-cc-pVTZ method. This combination of method/basis set adequately reproduces the relative benchmark CCSD(T) energy difference [Matus, M.; Dixon, D.; Peterson, K. A.; Harkless, J. A. W.; Francisco, J. S. J. Chem. Phys. 2007, 127, 174305] between these two isomers and, crucially, the fact that the D(2h) structure is a transition state linking two equivalent (mirror images) C(2v) isomers. The trajectories show that the symmetric open C(2v) isomers interconvert when passing through the D(2h) closed transition state structure and that, unlike tetraoxygen, no three-dimensional structures arise. The dynamic vibrational analysis yields peaks in good agreement with the static CCSD(T) harmonic frequencies and explains higher peaks as overtones, thus showing that unlike previous AIMD DFT-based approaches, carefully calibrated exchange-correlation functionals can produce reliable molecular dynamics results for complex PESs as the one corresponding to the lowest singlet of S(4).

Modelling the influence of hydrogen bond network on chemical shielding tensors description. GIAO-DFT study of WALP23 transmembrane alpha-helix as a test case.

Density Functional Theory (B3LYP/6-31G(d,p)) calculations of (15)N amide and (13)C carbonyl NMR chemical shielding tensors have been performed on WALP23trans-membrane alpha-helix peptide and compared to solid state NMR experiment performed on [(13)C(1)-Ala(13), (15)N-Leu(14)] specifically labelled peptide powder sample. Using either theoretical results obtained on the whole peptide or experimental data as reference, several simplest chemical models have been explored in order to reduce the computational cost while maintaining good theoretical accuracy. From this study, it appears that the hydrogen bond (N-H...O=C) network that exists in the alpha-helix has a major influence on the chemical shielding tensor and more specifically on the carbonyl (13)C sigma(22) eigenvalue. We show that a small truncated WALP_7 model is not adequate for (13)C(1) NMR description. The application of an external electric field in order to model the hydrogen bond network allows calculating chemical shielding tensors with accurate eigenvalues while the associated eigenvectors are largely modified. Finally, a 23 residues polyglycine peptide that includes the Alanine and Leucine residues for which NMR parameters must be calculated is proposed as the chemical model. This model is sufficient to mostly reproduce the calculation performed on WALP23 with major gain in computational time. Moreover, the application of a low intensity external electric field allows reaching the experimental accuracy for the determination of the eigenvalues.

Order parameters of a transmembrane helix in a fluid bilayer: case study of a WALP peptide.

A new solid-state NMR-based strategy is established for the precise and efficient analysis of orientation and dynamics of transmembrane peptides in fluid bilayers. For this purpose, several dynamically averaged anisotropic constraints, including (13)C and (15)N chemical shift anisotropies and (13)C-(15)N dipolar couplings, were determined from two different triple-isotope-labeled WALP23 peptides ((2)H, (13)C, and (15)N) and combined with previously published quadrupolar splittings of the same peptide. Chemical shift anisotropy tensor orientations were determined with quantum chemistry. The complete set of experimental constraints was analyzed using a generalized, four-parameter dynamic model of the peptide motion, including tilt and rotation angle and two associated order parameters. A tilt angle of 21 degrees was determined for WALP23 in dimyristoylphosphatidylcholine, which is much larger than the tilt angle of 5.5 degrees previously determined from (2)H NMR experiments. This approach provided a realistic value for the tilt angle of WALP23 peptide in the presence of hydrophobic mismatch, and can be applied to any transmembrane helical peptide. The influence of the experimental data set on the solution space is discussed, as are potential sources of error.

DFT 2H quadrupolar coupling constants of ruthenium complexes: a good probe of the coordination of hydrides in conjuction with experiments.

Transition metal (TM) hydrides are of great interest in chemistry because of their reactivity and their potential as catalysts for hydrogenation reactions. 2H solid-state NMR can be used in order to get information about the local environment of hydrogen atoms, and more particularly the coordination mode of hydrides in such complexes. In this work we will show that it is possible to establish at the level of density functional theory (DFT) a viable methodological strategy that allows the determination of 2H NMR parameters, namely the quadrupolar coupling constant (C(Q)) respectively the quadrupolar splitting (deltanuQ) and the asymmetry parameter (etaQ). The reliability of the method (B3PW91-DFT) and basis set effects have been first evaluated for simple organic compounds (benzene and fluorene). A good correlation between experimental and theoretical values is systematically obtained if the large basis set cc-pVTZ is used for the computations. 2H NMR properties of five mononuclear ruthenium complexes (namely Cp*RuD3(PPh3), Tp*RuD(THT)2, Tp*RuD(D2)(THT) and Tp*RuD(D2)2 and RuD2(D2)2(PCy3)2) which exhibit different ligands and hydrides involved in different coordination modes (terminal-H or eta2-H2), have been calculated and compared to previous experimental data. The results obtained are in excellent agreement with experiments. Although 2H NMR spectra are not always easy to analyze, assistance by quantum chemistry calculations allows unambiguous assignment of the signals of such spectra. As far as experiments can be achieved at very low temperatures in order to avoid dynamic effects, this hybrid theoretical/experimental tool may give useful insights in the context of the characterization of ruthenium surfaces or nanoparticles with solid-state NMR.

Propensity for local folding induced by the urea fragment in short-chain oligomers.

Examination of local folding and H-bonding patterns in model compounds can be extremely informative to gain insight into the propensity of longer-chain oligomers to adopt specific folding patterns (i.e. foldamers) based on remote interactions. Using a combination of experimental techniques (i.e. X-ray diffraction, FT-IR absorption and NMR spectroscopy) and theoretical calculations at the density functional theory (DFT) level, we have examined the local folding patterns induced by the urea fragment in short-chain aza analogues of beta- and gamma-amino acid derivatives. We found that the urea-turn, a robust C(8) conformation based on 1<--3 H-bond interaction, is largely populated in model ureidopeptides (I-IV) obtained by replacing the alpha-carbon of a beta-amino acid by a nitrogen. This H-bonding scheme is likely to compete with remote H-bond interactions, thus preventing the formation of secondary structures based on remote intrastrand interactions in longer oligomers. In related oligomers obtained by the addition of a methylene in the main chain (V-VIII), nearest-neighbour H-bonded interactions are unfavourable i.e. the corresponding C9 folding pattern is hardly populated. In this series, folding based on remote intrastrand interactions becomes possible for longer oligomers. We present spectroscopic evidence that tetraurea VIII is likely to be the smallest unit capable of reproducing the H-bonded motif found in 2.5-helical N,N'-linked oligoureas.

Ab initio dynamic study of the reaction of Cl2LaR (R=H, CH3) with H2.

In this paper, a comparison between "static" and "dynamic" determination of the thermodynamic (DeltarF degrees) and kinetic data (DeltarF#) for the reaction of Cl2LaR (R=H, CH3) and H2 is given. A difference is obtained in the case of the reaction between Cl2LaH and H2 and can be attributed to a failure of the "static" approach based on the harmonic approximation. The influence of the zero point energy correction is also analyzed but does not explain the 30% difference between the two calculated activation energies. The influence of the flatness of the potential energy surface around the transition state is proved as no such an effect is observed for the reaction of Cl2LaCH3 and H2.