Polarization spectroscopy methods in the determination of interactions of small molecules with nucleic acids – tutorial

• Tamara Šmidlehner,
• Ivo Piantanida and
• Gennaro Pescitelli

Beilstein J. Org. Chem. 2018, 14, 84–105, doi:10.3762/bjoc.14.5

Aminosugar-based immunomodulator lipid A: synthetic approaches

• Alla Zamyatina

Beilstein J. Org. Chem. 2018, 14, 25–53, doi:10.3762/bjoc.14.3

• cytokines, chemokines, prostaglandins and reactive oxygen species which manifest an acute inflammatory response to infection. The “endotoxic principle” of LPS resides in its amphiphilic membrane-bound fragment glycophospholipid lipid A which directly binds to the TLR4·MD-2 receptor complex. The lipid A

• major surface antigen of Gram-negative bacteria, a complex heterogeneous glycolipid lipopolysaccharide (LPS, or endotoxin) [2][3], is recognised by a receptor complex composed of Toll-like Receptor 4 (TLR4) and a co-receptor protein myeloid differentiation factor 2 (MD-2) which are expressed by

• micro-heterogeneous structure distinguished by three regions: the lipid A [5], the core oligosaccharide [6] and the O-antigen [7] (Figure 1B). The TLR4·MD-2 receptor complex senses picomolar amounts of LPS and initiates the biosynthesis of diverse mediators of inflammation (such as tumor necrosis factor

The use of 4,4,4-trifluorothreonine to stabilize extended peptide structures and mimic β-strands

• Yaochun Xu,
• Isabelle Correia,
• Tap Ha-Duong,
• Nadjib Kihal,
• Jean-Louis Soulier,
• Julia Kaffy,
• Benoît Crousse,
• Olivier Lequin and
• Sandrine Ongeri

Beilstein J. Org. Chem. 2017, 13, 2842–2853, doi:10.3762/bjoc.13.276

• according to their central fluorinated or non-fluorinated residue, all-atom molecular dynamics (MD) simulations were performed using the GROMACS 4.5 package, with the OPLS-AA force field in combination with the SPC/E water model (for a complete description of the method, see Supporting Information File 1

• -Hα coupling values are in fair agreement with the experimental ones, indicating that the peptide conformational ensembles were sampled quite faithfully by the MD trajectories. Excepting the first residue Ala1, all the theoretical coupling constants have high values above 7 Hz, confirming that the

• pentapeptides have locally extended backbone conformations. It could be noted that the 3JHN-Hα experimental value of the central residue in compounds 3a, 3b, and 4b are significantly higher than in the simulations. This discrepancy between the NMR and MD 3JHN-Hα coupling values for the fluorinated central

Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres

• Myriam Drouin and
• Jean-François Paquin

Beilstein J. Org. Chem. 2017, 13, 2637–2658, doi:10.3762/bjoc.13.262

• fluorinated derivatives against three HIV strains. The number indicates the position of the dipeptide isostere. Acknowledgements We acknowledge the financial support of NSERC, PROTEO and Université Laval. MD thanks NSERC for a Vanier Canada Graduate Scholarship.

What contributes to an effective mannose recognition domain?

• Christoph P. Sager,
• Deniz Eriş,
• Martin Smieško,
• Rachel Hevey and
• Beat Ernst

Beilstein J. Org. Chem. 2017, 13, 2584–2595, doi:10.3762/bjoc.13.255

• well as the influence of highly mobile vs conserved waters were analyzed. For the assessment of the dynamic behavior of the ligand complexes of the seven calcium-dependent lectins, 20 ns molecular dynamics (MD) simulations were performed [57]. The most prominent interactions of O–C3 and O–C4 of the

• calcium ions. During MD simulations, the number of ligand–protein hydrogen-bond interactions for lectins A–F varied from 1.5 to 3.5, and subsequently increased to 4.5 and 5.4 for LecB (G) and BC2L-A (H), respectively. Lastly, FimH (I) forms on average 7.9 hydrogen bonds with methyl α-D-mannopyranoside (2

• ). For H-bonds that were only partially present during the MD simulation, non-integer numbers of hydrogen bonds arise. The number of water-bridged H bonds between ligand and lectin varied greatly (Figure 3), from 0.1 to 2.4 for the buried binding site of BC2L-A (H) versus the solvent exposed binding site

2-Methyl-2,4-pentanediol (MPD) boosts as detergent-substitute the performance of ß-barrel hybrid catalyst for phenylacetylene polymerization

• Julia Kinzel,
• Daniel F. Sauer,
• Marco Bocola,
• Marcus Arlt,
• Tayebeh Mirzaei Garakani,
• Andreas Thiel,
• Klaus Beckerle,
• Tino Polen,
• Jun Okuda and
• Ulrich Schwaneberg

Beilstein J. Org. Chem. 2017, 13, 1498–1506, doi:10.3762/bjoc.13.148

•  1). Molecular dynamics (MD) simulations reveal an optimal minimum number of ≈200 MPD molecules for shielding the hydrophobic transmembrane region of FhuA ΔCVFtev MD simulations of FhuA ΔCVFtev were performed in a box with varying numbers of MPD molecules from 126 MPD, 189 MPD, 252 MPD to 378 MPD

• molecules start to cluster around the hydrophobic transmembrane region. Membrane proteins are normally stabilized by incorporation in a protecting membrane layer formed by ionic detergent molecules such as lipids, SDS or nonionic glycolipids. In contrast, in MD simulations with the two highest

• FhuA ΔCVFtev (see MD simulation results, Figure 2C and D), ensuring the long-term stability of the protein (Figure S1, Supporting Information File 1). The aforementioned features are consistent with results from circular dichroism (CD) spectroscopy (Figure S1, Supporting Information File 1), showing

G-Protein coupled receptors: answers from simulations

• Timothy Clark

Beilstein J. Org. Chem. 2017, 13, 1071–1078, doi:10.3762/bjoc.13.106

• Timothy Clark Computer-Chemie-Centrum, Department of Chemistry and Pharmacy, Friedrich-Alexander-University Erlangen-Nuernberg, Naegelsbachstr. 25, 91052 Erlangen, Germany 10.3762/bjoc.13.106 Abstract Molecular-dynamics (MD) simulations are playing an increasingly important role in research into

• the modes of action of G-protein coupled receptors (GPCRs). In this field, MD simulations are unusually important as, because of the difficult experimental situation, they often offer the only opportunity to determine structural and mechanistic features in atomistic detail. Modern combinations of soft

• - and hardware have made MD simulations a powerful tool in GPCR research. This is important because GPCRs are targeted by approximately half of the drugs on the market, so that computer-aided drug design plays a major role in GPCR research. Keywords: computer-aided drug design; GPCR; metadynamicxs

Membrane properties of hydroxycholesterols related to the brain cholesterol metabolism

• Malte Hilsch,
• Ivan Haralampiev,
• Peter Müller,
• Daniel Huster and
• Holger A. Scheidt

Beilstein J. Org. Chem. 2017, 13, 720–727, doi:10.3762/bjoc.13.71

• estradiol was found in the lipid water interface of the membrane with an orientation perpendicular to the membrane normal. By that, the molecules act disturbing rather than ordering. Notably, MD simulations found an opposite effect of the hydroxycholesterols [21]. The additional polarity of

• proteins) is impacted. MD simulations for 27-HC have shown, that this molecule adopts compared to cholesterol different orientations within the membrane, which are upside-down, largely tilted and/or inter-leaflet positions [21]. These properties indicate that the molecules are less strongly anchored within

Inclusion complexes of β-cyclodextrin with tricyclic drugs: an X-ray diffraction, NMR and molecular dynamics study

• Franca Castiglione,
• Fabio Ganazzoli,
• Luciana Malpezzi,
• Andrea Mele,
• Walter Panzeri and
• Giuseppina Raffaini

Beilstein J. Org. Chem. 2017, 13, 714–719, doi:10.3762/bjoc.13.70

• /β-CD and 2/β-CD complexes, with the aromatic ring system entering the cavity from the large rim of the cyclodextrin and the alkylammonium chain protruding out of the cavity and facing the secondary OH rim. These features matched those found in the molecular dynamics (MD) simulations in solution and

• in the solid state from single-crystal X-ray diffraction of 1/β-CD and 2/β-CD complexes. The latter complex was found in a single conformation in the solid state, whilst the MD simulations in explicit water reproduced the conformational transitions observed experimentally for the free molecule

• . Keywords: amitriptyline; β-cyclodextrin; crystal structure; cyclobenzaprine; molecular dynamics simulations; NOE; Introduction The present paper reports on a multidisciplinary approach [1][2] based on single crystal X-ray diffraction, solution NMR spectroscopy and molecular dynamics (MD) simulations with

Synthesis and evaluation of anti-oxidant and cytotoxic activities of novel 10-undecenoic acid methyl ester based lipoconjugates of phenolic acids

• Naganna Narra,
• Shiva Shanker Kaki,
• Rachapudi Badari Narayana Prasad,
• Sunil Misra,
• Koude Dhevendar,
• Venkateshwarlu Kontham and
• Padmaja V. Korlipara

Beilstein J. Org. Chem. 2017, 13, 26–32, doi:10.3762/bjoc.13.4

• different cancer cell lines viz., MDA-MB-231, breast cancer (ATCC® HTB-26™); SKOV3, ovarian cancer (ATCC® HTB-77™); MCF7, breast cancer (ATCC® HTB-22™); DU 145, prostate cancer (ATCC® HTB-81™); HepG2, liver hepatocellular carcinoma (ATCC® HB-8065™) were obtained from the ATCC (Bethesda, MD, USA) and

Computational methods in drug discovery

• Sumudu P. Leelananda and
• Steffen Lindert

Beilstein J. Org. Chem. 2016, 12, 2694–2718, doi:10.3762/bjoc.12.267

• , agonists, inhibitors, etc. of a target) design. Molecular dynamics (MD) simulations are frequently used in SBDD to give insights into not only how ligands bind with target proteins but also the pathways of interaction and to account for target flexibility. This is especially important when drug targets are

• reported for HIV integrase. MD simulations that were performed with the holo-structure of HIV integrase bound to a known ligand showed signs of a novel binding pocket opening in close proximity to its active site [183]. RCS ligand docking showed that this binding site is a possible binding pocket for drug

• use enhanced sampling methods. One of the tools that is extensively and routinely used to understand protein motions and conformational space that is accessible for protein structures is molecular dynamics (MD) simulations [190]. The most widely used molecular dynamics software packages are NAMD [191

Biomimetic synthesis and HPLC–ECD analysis of the isomers of dracocephins A and B

• Viktor Ilkei,
• András Spaits,
• Anita Prechl,
• Áron Szigetvári,
• Zoltán Béni,
• Miklós Dékány,
• Csaba Szántay Jr,
• Judit Müller,
• Árpád Könczöl,
• Ádám Szappanos,
• Attila Mándi,
• Sándor Antus,
• Ana Martins,
• Attila Hunyadi,
• György Tibor Balogh,
• György Kalaus (†),
• Hedvig Bölcskei,
• László Hazai and
• Tibor Kurtán

Beilstein J. Org. Chem. 2016, 12, 2523–2534, doi:10.3762/bjoc.12.247

• or 90:10 with 0.1% TFA additive to set the pH to about 2 at a flow rate of 1.0 mL/min for 2 and 3. HPLC–UV and OR chromatograms were measured with Jasco MD-910 multiwavelength and OR-2090Plus chiral detectors, respectively. The HPLC–ECD traces were recorded at the specified wavelength with a Jasco J

Is conformation a fundamental descriptor in QSAR? A case for halogenated anesthetics

• Maria C. Guimarães,
• Mariene H. Duarte,
• Josué M. Silla and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2016, 12, 760–768, doi:10.3762/bjoc.12.76

• descriptors (MD) for correlation with bioactivity values. This is not a simple task because the bioactive conformation in molecule data sets is usually unknown and, therefore, optimized structures in a receptor-free environment are often used to generate the MD´s. In this case, a wrong conformational choice

• suggesting that these 2D MD´s can be advantageous over some three-dimensional descriptors. Keywords: conformational analysis; isoflurane; QSAR; theoretical calculations; volatile anesthetics; Introduction Quantitative structure–activity relationship (QSAR) studies try to find a correlation between chemical

• structures and the corresponding bioactivities by means of molecular descriptors (MD´s). In this way, molecular architecture and substitution patterns in a series of congeneric molecules are described by calculable or empirical data having some relationship with biological activity, becoming the technique

Dynamic behavior of rearranging carbocations – implications for terpene biosynthesis

• Stephanie R. Hare and
• Dean J. Tantillo

Beilstein J. Org. Chem. 2016, 12, 377–390, doi:10.3762/bjoc.12.41

• [31][32][33][34]. To acquire evidence for non-statistical dynamic effects, molecular dynamics (MD) simulations are run for a statistically relevant number of trajectories (typically on the order of hundreds or thousands, depending on the system and the starting point for trajectories) [35][36]. The

• questions. MD simulations have been employed to answer two different questions about the chemical reactions discussed below: (1) what mechanism(s) is energetically viable? and (2) do (non-statistical) dynamic effects exert control over product distributions? While trajectories can be started from anywhere

• minimum, however, is that there is no guarantee the trajectories are going to be “productive”. This creates an operational problem in most cases because, relative to the optimization of stationary points on a PES, MD trajectories are very computationally expensive, a result of having to repeatedly

Aggregation behavior of amphiphilic cyclodextrins in a nonpolar solvent: evidence of large-scale structures by atomistic molecular dynamics simulations and solution studies

• Giuseppina Raffaini,
• Fabio Ganazzoli and
• Antonino Mazzaglia

Beilstein J. Org. Chem. 2016, 12, 73–80, doi:10.3762/bjoc.12.8

• the eight molecules clustered in a single but still relatively loose aggregate. In the subsequent long MD run that was eventually carried out for a total of 100 ns, the two aggregates obtained by these preliminary energy minimizations turned out to be quite stable, enhancing the intermolecular

• last part of the MD run when no change was detected in the energy components (i.e., the intramolecular terms, the van der Waals component and the electrostatic one due to the dipolar interactions) showed that the first aggregate is more stable than the other one by about 1.32 ± 0.19 MJ, where the

• ± sign refers to the value calculated from the standard deviations of the average potential energy values due to the thermal fluctuations. However, the very large stability of each aggregate within the MD run indicates that both are very robust conformations that may form at least for kinetic reasons and

Physical properties and biological activities of hesperetin and naringenin in complex with methylated β-cyclodextrin

• Waratchada Sangpheak,
• Jintawee Kicuntod,
• Roswitha Schuster,
• Thanyada Rungrotmongkol,
• Peter Wolschann,
• Nawee Kungwan,
• Helmut Viernstein,
• Monika Mueller and
• Piamsook Pongsawasdi

Beilstein J. Org. Chem. 2015, 11, 2763–2773, doi:10.3762/bjoc.11.297

• ) complexes had reached equilibration at 25 ns. The 30 MD snapshots from the last 55 ns of each simulation was selected for binding free energy calculations in accordance with the naringenin/CDs complexes [40]. In this study, we applied a molecular mechanics and continuum solvation method to estimate the

• to MM energy. To correct this energy section, the same set of 25 to 80 MD snapshots was carried out by the single point DFT M062X/6-31+g (d,p) calculation in this study. The results of QM/PBSA and QM/GBSA binding free energies were in agreement with MM/PBSA and MM/GBSA energies. The experimental ∆G

• Molecular dynamics (MD) simulations with periodic boundary condition were performed on the three best docked structures of the hesperetin/CDs complexes (Figure 7) similar to our previous studies on naringenin/CDs complexes [40][60] using the Amber 12 software package [61]. Note that the docked structures

Aggregation behaviour of amphiphilic cyclodextrins: the nucleation stage by atomistic molecular dynamics simulations

• Giuseppina Raffaini,
• Antonino Mazzaglia and
• Fabio Ganazzoli

Beilstein J. Org. Chem. 2015, 11, 2459–2473, doi:10.3762/bjoc.11.267

• = OH), simply denoted in the following as the model aCD. The simulations used molecular mechanics (MM) and molecular dynamics (MD) methods, and were carried out both in vacuo, to mimic a non-polar and weakly interacting solvent, and in explicit water, using a box of water molecules with periodic

• boundary conditions (PBC). While MM methods involve energy minimizations of the simulated systems with respect to all the atomic coordinates, the MD methods describe the time evolution of the whole system at the chosen temperature, according to Newton’s equation of motion, thus following the kinetics of a

• of the molecules in solution, and then we perform MD runs of these geometries until equilibrium, monitored inter alia through the system energy and its components, and through the intermolecular separations, is achieved. Eventually, we carry out final optimizations of different conformations saved

Bromotyrosine-derived alkaloids from the Caribbean sponge Aplysina lacunosa

• Qun Göthel,
• Thanchanok Sirirak and
• Matthias Köck

Beilstein J. Org. Chem. 2015, 11, 2334–2342, doi:10.3762/bjoc.11.254

• . Experimental UV spectra were recorded during HPLC separation with a DAD detector (JASCO MD-2010 Plus). CD spectra were recorded on a JASCO J-810 spectropolarimeter. Low and high resolution ESIMS was performed with a Bruker micrOTOFLC mass spectrometer. Mass calibration was performed using sodium formate

Co-solvation effect on the binding mode of the α-mangostin/β-cyclodextrin inclusion complex

• Chompoonut Rungnim,
• Sarunya Phunpee,
• Manaschai Kunaseth,
• Supawadee Namuangruk,
• Kanin Rungsardthong,
• Thanyada Rungrotmongkol and
• Uracha Ruktanonchai

Beilstein J. Org. Chem. 2015, 11, 2306–2317, doi:10.3762/bjoc.11.251

• anion affinity and selectivity of a neutral anion receptor, bis(cyclopeptide) [17]. Molecular dynamics (MD) simulations can give important insights into the energetics of structural interactions. The hydrated structure of β-CD in aqueous solution [18] and those showing host–guest interactions between

• the β-CD structure and guest molecules in its inclusion compounds have been reported [19][20][21]. Moreover, MD simulations of β-CD in water and ethanol mixtures have been performed to investigate the orientation of the co-solvent in the hydrophobic cavity of the β-CD [22]. Recently, Biedermann et al

• . [23] reviewed the hydrophobic effect of supramolecular complexes from MD simulation studies and emphasized that the non-covalent driving force of high-energy water in the cavity of cyclodextrins, cyclophanes and cucurbiturils was an essential factor for complexation with the guest molecule. MD

Coupling of α,α-difluoro-substituted organozinc reagents with 1-bromoalkynes

• Artem A. Zemtsov,
• Alexander D. Volodin,
• Vitalij V. Levin,
• Marina I. Struchkova and
• Alexander D. Dilman

Beilstein J. Org. Chem. 2015, 11, 2145–2149, doi:10.3762/bjoc.11.231

• mechanism. Optimization studies. Reaction of organozinc compounds 2 with bromoalkynes 3. Supporting Information Supporting Information File 454: Full experimental details, compound characterization, and copies of NMR spectra. Acknowledgements This work was supported by the Ministry of Science (project MD

Peptide–polymer ligands for a tandem WW-domain, an adaptive multivalent protein–protein interaction: lessons on the thermodynamic fitness of flexible ligands

• Katharina Koschek,
• Vedat Durmaz,
• Oxana Krylova,
• Marek Wieczorek,
• Shilpi Gupta,
• Martin Richter,
• Alexander Bujotzek,
• Christina Fischer,
• Rainer Haag,
• Christian Freund,
• Marcus Weber and
• Jörg Rademann

Beilstein J. Org. Chem. 2015, 11, 837–847, doi:10.3762/bjoc.11.93

• generated randomly with the aid of a probabilistic hPG building algorithm as described previously [23]. After some preparatory relaxation steps, each of the three polymers underwent three explicit solvent molecular dynamics (MD) simulations of 100 ns length serving as production runs. The first 30% of the

• multivalent peptide-polymer conjugates and the tandem WW domain of protein FBP21 determined at 8 °C by ITC measurements. MD simulations over time (0–100 ns) yielding A) the mean sulfur distance between two peptides at their linking site, B) the mean nitrogen distance between two peptides at the farthest

• distance between peptide and polymer chain C) the frequency of observed peptide–polymer distances in dependence of the polymer backbone pHPMA, hPG and dextran, respectively. MD simulation image showing the interaction of two dextran–peptide conjugates with three tandem WW domains of FBP21 illustrating the

Articulated rods – a novel class of molecular rods based on oligospiroketals (OSK)

• Pablo Wessig,
• Roswitha Merkel and
• Peter Müller

Beilstein J. Org. Chem. 2015, 11, 74–84, doi:10.3762/bjoc.11.11

• equilibrium of articulated rods The fundamental feature of articulated rods is the restricted conformational space with two dominating species: a stretched and a folded conformation. This feature was concluded from Molecular Dynamics (MD) simulation revealing a bimodal distribution of the end-to-end distance

Synthesis and characterization of a new photoinduced switchable β-cyclodextrin dimer

• Florian Hamon,
• Claire Blaszkiewicz,
• Marie Buchotte,
• Estelle Banaszak-Léonard,
• Hervé Bricout,
• Sébastien Tilloy,
• Eric Monflier,
• Christine Cézard,
• Laurent Bouteiller,
• Christophe Len and
• Florence Djedaini-Pilard

Beilstein J. Org. Chem. 2014, 10, 2874–2885, doi:10.3762/bjoc.10.304

• parameterized according to the strategy previously developed using the RED program [47] along with the RED server [48]. Molecular dynamics (MD) simulations were performed using the SANDER module of the AMBER10 program suite to perform MD simulations on the aforementioned complexes [49]. The systems were

• solvated in a truncated octahedral box with a buffer distance of 10.0 Å. The q4md-CD force field parameters were used to model the β-CD systems [45]. The parameters used for water were taken from the TIP3P model [50]. Classic MD simulations of 50 ns were then performed using the NPT ensemble at a pressure

• of 1 atm and a temperature of 300 K. In order to obtain representative ensembles of conformations for the two bis-CD systems, molecular configurations from MD trajectories were clustered. Ab initio calculations were performed with the Gaussian 09 program [50] to perform quantum chemical calculations

Binding mode and free energy prediction of fisetin/β-cyclodextrin inclusion complexes

• Bodee Nutho,
• Wasinee Khuntawee,
• Chompoonut Rungnim,
• Piamsook Pongsawasdi,
• Peter Wolschann,
• Alfred Karpfen,
• Nawee Kungwan and
• Thanyada Rungrotmongkol

Beilstein J. Org. Chem. 2014, 10, 2789–2799, doi:10.3762/bjoc.10.296

• to investigate the preferential binding mode and encapsulation of the flavonoid fisetin in the nano-pore of β-cyclodextrin (β-CD) at the molecular level using various theoretical approaches: molecular docking, molecular dynamics (MD) simulations and binding free energy calculations. The molecular

• docking suggested four possible fisetin orientations in the cavity through its chromone or phenyl ring with two different geometries of fisetin due to the rotatable bond between the two rings. From the multiple MD results, the phenyl ring of fisetin favours its inclusion into the β-CD cavity, whilst less

• stability against exposure to strong UV light and high temperatures [24][25]. In recent years, computational approaches have played a significant role in monitoring inclusion complexation between cyclodextrin and guest molecules [26][27] at the molecular level [28][29]. Molecular dynamics (MD) simulations

Specific DNA duplex formation at an artificial lipid bilayer: fluorescence microscopy after Sybr Green I staining

• Emma Werz and
• Helmut Rosemeyer

Beilstein J. Org. Chem. 2014, 10, 2307–2321, doi:10.3762/bjoc.10.240

• )- calculations of lipid–nucleic acid complexes with MC and MD simulations of semi-quantitative, “course-grained” models (CGM) are going to be performed (Prof. Dr. Philipp Maass, Department of Statistical Physics, University of Osnabrück). Studies described in this manuscript as well as of those of a forthcoming