Anti Conformation Research Articles

Electrostatic CH-π Interactions Can Override Fluorine Gauche Effects To Exert Conformational Control.

Fluorine gauche effects are conformational properties of 2-fluoroethanes often applied in modern molecular designs. However, the physical origins of fluorine gauche effects are not well understood, with the consensus favoring the established hyperconjugation theory over an emerging electrostatic model. Using a series of model systems, we show that a shift to fluorine gauche effects can be influenced by intramolecular CH⋅⋅⋅π aromatic interactions, a through-space event. Modulating the π-ring (forming the aromatic interaction) with substituent groups resulted in a linear Hammett relationship, thus indicating that the CH⋅⋅⋅π interaction has electrostatic features. For instance, attaching a nitro group (an electron-withdrawing substituent) to the π-ring weakened the CH⋅⋅⋅π interaction and led to a gauche preference, whereas an anti conformer is preferred with amine as substituent. The experimental results performed by using proton NMR spectroscopy are corroborated by gas-phase DFT calculations and solid-state X-ray crystallography.

Hoogsteen Base Pairings

In contrast to Watson-Crick (WC) base pairing, Hoogsteen (HG) base pairing involves flipping a purine base 180° between its anti and syn conformation. Recent studies have shown that HG pairs coexist in dynamical equilibrium, and several biological functions depend on them. This significance has stirred computational research on this base-pairing transition. However, a methodical reproduction of sequence variations has continued to be out of reach. It is becoming increasingly clear that Hoogsteen base pairs play a crucial role in DNA replication, recognition, damage repair, and incorrect sequence repair. The Protein Data Bank contains a variety of Hoogsteen base pairing modes that include the preference for A–T versus G–C bps, TA versus GG steps, and a preference for 5'-purines at terminal ends. RNA A-form duplexes are strongly disfavored by Hoogsteen base pairs, in stark contrast to B-form DNA. Therefore, N1-methyl adenosine and N1-methyl guanosine, which transpire in DNA as alkylation impairment and in RNA as posttranscriptional adjustments, have great differences in effects. They create G–C+ and A–U Hoogsteen base pairs in duplex DNA that preserve the structural integrity of the double helix, but obstruct base pairing altogether and induce local duplex melting in RNA, providing a mechanism for potently disrupting RNA structure through posttranscriptional modifications. In duplex DNA, they maintain the structural integrity of the double helix by creating G–C+ and A–U Hoogsteen base pairs, but block base pairing altogether and cause local duplex melting in RNA, thus providing a potent means for disrupting RNA structure post transcriptionally. As a result of the markedly different inclinations for B-DNA and A-RNA to form Hoogsteen base pairs, they may be able to balance the opposing demands of maintaining genome stability and dynamically modulating the epitranscriptome. This review examines the occurrence of Hoogsteen base pairs in DNA and RNA duplexes.

Structural Properties of Hachimoji Nucleic Acids and Their Building Blocks: Comparison of Genetic Systems with Four, Six and Eight Alphabets.

Expansion of the genetic alphabet is an ambitious goal. A recent breakthrough has led to the eight-base (hachimoji) genetics having canonical and unnatural bases. However, very little is known on the molecular-level features that facilitate the candidature of unnatural bases as genetic alphabets. Here we amalgamated DFT calculations and MD simulations to analyse the properties of the constituents of hachimoji DNA and RNA. DFT reveals the dominant syn conformation for isolated unnatural deoxyribonucleosides and at the 5'-end of oligonucleotides, although an anti/syn mixture is predicted at the nonterminal and 3'-terminal positions. However, isolated ribonucleotides prefer an anti/syn mixture, but mostly prefer anti conformation at the nonterminal positions. Further, the canonical base pairing combinations reveals significant strength, which may facilitate replication of hachimoji DNA. We also identify noncanonical base pairs that can better tolerate the substitution of unnatural pairs in RNA. Stacking strengths of 51 dimers reveals higher average stacking stabilization of dimers of hachimoji bases than canonical bases, which provides clues for choosing energetically stable sequences. A total of 14.4 μs MD simulations reveal the influence of solvent on the properties of hachimoji oligonucleotides and point to the likely fidelity of replication of hachimoji DNA. Our results pinpoint the features that explain the experimentally observed stability of hachimoji DNA.

Structure of the major oxidative damage 7,8-dihydro-8-oxoguanine presented into a catalytically competent DNA glycosylase.

If left unrepaired, the major oxidative DNA lesion 7,8-dihydro-8-oxoguanine (oxoG) promotes G-to-T transversions by favorably adopting a syn conformation and base pairing with dATP during replication. The human oxoG DNA glycosylase hOGG1 senses and removes oxoG amid millions-fold excess of guanine, thereby counteracting the genotoxic effects of the major oxidative damage. Crystal structures of hOGG1 in complex with oxoG-containing DNA have provided key insights into the lesion recognition and catalysis mechanisms of the enzyme. These lesion-recognition complex (LRC) structures typically involve a catalytically inactive hOGG1 mutant, where one of the catalytic-site amino acid residues is mutated to prevent the cleavage of oxoG. The use of a catalytically incompetent hOGG1 mutant has thus precluded understanding of unscathed interactions between oxoG and hOGG1 catalytic site as well as interactions among catalytic-site amino acid residues. As an orthogonal approach to visualize such interactions, we have co-crystallized a catalytically competent hOGG1 bound to 2'-fluoro-oxodG-containing DNA, a transition state destabilizing inhibitor that binds hOGG1 but is not processed by the enzyme. In this fluorinated lesion-recognition complex (FLRC), the 8-oxo moiety of oxoG is recognized by Gly42 and the Watson-Crick edge of oxoG is contacted by Gln315 and Pro266. The previously observed salt bridge between Lys249 and Cys253 is lacking in the FLRC, suggesting Lys249 is primed by Cys253 and poised for nucleophilic attack on C1' of oxodG. Overall, hOGG1 FLRC marks the first structure of oxoG presented into an intact catalytic site of hOGG1 and provides complementary insights into the glycosylase mechanisms of the enzyme.

Simultaneous Tunneling Control in Conformer-Specific Reactions.

We present here a new example of chemical reactivity governed by quantum tunneling, which also highlights the limitations of the classical theories. The syn and anti conformers of a triplet 2-formylphenylnitrene, generated in a nitrogen matrix, were found to spontaneously rearrange to the corresponding 2,1-benzisoxazole and imino-ketene, respectively. The kinetics of both transformations were measured at 10 and 20 K and found to be temperature-independent, providing clear evidence of concomitant tunneling reactions (heavy-atom and H-atom). Computations confirm the existence of these tunneling reaction pathways. Although the energy barrier between the nitrene conformers is lower than any of the observed reactions, no conformational interconversion was observed. These results demonstrate an unprecedented case of simultaneous tunneling control in conformer-specific reactions of the same chemical species. The product outcome is impossible to be rationalized by the conventional kinetic or thermodynamic control.

A perphenylated PSi4P-chain: Synthesis and characterization of 1,4-bis(diphenylphosphanyl)octaphenyl-n-tetrasilane

The linear 1,4-bis(diphenylphosphanyl)octaphenyl-n-tetrasilane was prepared starting from chlorodiphenylphosphane and 1,4-dilithiooctaphenyl-n-tetrasilane, Li(SiPh2)4Li. The latter one was made from cyclo-(SiPh2)5 and lithium. The title compound was obtained in moderate yield and characterized by IR, Raman, UV, 31P, 29Si, and 1H NMR spectroscopy. The crystal structure analysis of the title compound shows a perfect anti conformation (180°) for the central Si-Si-Si-Si unit. The silicon-silicon and the silicon-phosphorus bonds are elongated. This is caused by the complete substitution of the molecule by sterically demanding phenyl-substituents and effective σ-conjugation along the main chain.

ADAR activation by inducing a syn conformation at guanosine adjacent to an editing site.

ADARs (adenosine deaminases acting on RNA) can be directed to sites in the transcriptome by complementary guide strands allowing for the correction of disease-causing mutations at the RNA level. However, ADARs show bias against editing adenosines with a guanosine 5' nearest neighbor (5'-GA sites), limiting the scope of this approach. Earlier studies suggested this effect arises from a clash in the RNA minor groove involving the 2-amino group of the guanosine adjacent to an editing site. Here we show that nucleosides capable of pairing with guanosine in a syn conformation enhance editing for 5'-GA sites. We describe the crystal structure of a fragment of human ADAR2 bound to RNA bearing a G:G pair adjacent to an editing site. The two guanosines form a Gsyn:Ganti pair solving the steric problem by flipping the 2-amino group of the guanosine adjacent to the editing site into the major groove. Also, duplexes with 2'-deoxyadenosine and 3-deaza-2'-deoxyadenosine displayed increased editing efficiency, suggesting the formation of a Gsyn:AH+anti pair. This was supported by X-ray crystallography of an ADAR complex with RNA bearing a G:3-deaza dA pair. This study shows how non-Watson-Crick pairing in duplex RNA can facilitate ADAR editing enabling the design of next generation guide strands for therapeutic RNA editing.

Conformational Preferences of Pyridone Adenine Dinucleotides from Molecular Dynamics Simulations.

Pyridone adenine dinucleotides (ox-NADs) are redox inactive derivatives of the enzyme cofactor and substrate nicotinamide adenine dinucleotide (NAD) that have a carbonyl group at the C2, C4, or C6 positions of the nicotinamide ring. These aberrant cofactor analogs accumulate in cells under stress and are potential inhibitors of enzymes that use NAD(H). We studied the conformational landscape of ox-NADs in solution using molecular dynamics simulations. Compared to NAD+ and NADH, 2-ox-NAD and 4-ox-NAD have an enhanced propensity for adopting the anti conformation of the pyridone ribose group, whereas 6-ox-NAD exhibits greater syn potential. Consequently, 2-ox-NAD and 4-ox-NAD have increased preference for folding into compact conformations, whereas 6-ox-NAD is more extended. ox-NADs have distinctive preferences for the orientation of the pyridone amide group, which are driven by intramolecular hydrogen bonding and steric interactions. These conformational preferences are compared to those of protein-bound NAD(H). Our results may help in identifying enzymes targeted by ox-NADs.

Iterative synthesis, structures, and properties of acyclic and cyclic acridone oligomers

AbstractAcyclic and cyclic acridone‐2,7‐diyl oligomers were synthesized by an iterative procedure from 10‐mesitylacridone as heteroatom containing π‐conjugated compounds. The oligomeric chain was elongated by a combination of regioselective bromination, borylation, Ni(0)‐mediated homocoupling, and Suzuki‐Miyaura coupling up to acyclic hexamer. Subsequently, the cyclic hexamer was synthesized by the bromination and intramolecular coupling of the acyclic hexamer. The DFT calculations revealed that the acyclic oligomers preferred to take extended structures with anti conformations, whereas the cyclic hexamer took a macrocyclic structure with syn conformations. The UV/Vis and fluorescence spectra of the series of oligomers were measured, and the effects of the chain length and the cyclization are discussed in terms of π‐conjugation.

Reorganization of the intramolecular hydrogen bonding network in 1,14-di(arylamino)-5,10-di(ethoxycarbonyl)-tripyrrins

Recently we have reported that 1,14-diaminated tripyrrins form a double helical structure via interstrand hydrogen bonding interaction in non-polar solvents. In this work, ethoxycarbonyl-substituted 1,14-di(arylamino)tripyrrins were prepared by nucleophilic substitution reaction. The structure has been revealed by X-ray analysis to be a ([Formula: see text]-syn, [Formula: see text]-syn) conformer stabilized by intramolecular hydrogen bonding between the pyrrolic NH proton and the ester carbonyl oxygen atom. This conformer was likely formed as a meta-stable state in solution since thermal isomerization into a ([Formula: see text]-syn, [Formula: see text]-syn) conformer was observed in DMSO via NH tautomerization.

Iodine Gauche Effect Induced by an Intramolecular Hydrogen Bond.

The gauche conformer in 1-X,2-Y-disubstituted ethanes, that is, the staggered orientation in which X and Y are in closer contact, is only favored for relatively small substituents that do not give rise to large X···Y steric repulsion. For more diffuse substituents, weakly attractive orbital interactions between antiperiplanar bonds (i.e., hyperconjugation) cannot overrule the repulsive forces between X and Y. Our quantum chemical analyses of the rotational isomerism of XCH2CH2Y (X = F, OH; Y = I) at ZORA-BP86-D3(BJ)/QZ4P reveal that indeed the anti conformer is generally favored due to a less destabilizing I···F and I···O-H steric repulsion. The only case when the gauche conformer is preferred is when the hydroxyl hydrogen is oriented toward the iodine atom in the 2-iodoethanol. This is because of the significantly stabilizing covalent component of the I···H-O intramolecular hydrogen bond. Therefore, we show that strong intramolecular interactions can overcome the steric repulsion between bulky substituents in 1,2-disubstituted ethanes and cause the gauche effect. Our quantum chemical computations have guided nuclear magnetic resonance experiments that confirm the increase in the gauche population as X goes from F to OH.

Molecular Simulations Matching Denaturation Experiments for N6-Methyladenosine.

Post-transcriptional modifications are crucial for RNA function and can affect its structure and dynamics. Force-field-based classical molecular dynamics simulations are a fundamental tool to characterize biomolecular dynamics, and their application to RNA is flourishing. Here, we show that the set of force-field parameters for N6-methyladenosine (m6A) developed for the commonly used AMBER force field does not reproduce duplex denaturation experiments and, specifically, cannot be used to describe both paired and unpaired states. Then, we use reweighting techniques to derive new parameters matching available experimental data. The resulting force field can be used to properly describe paired and unpaired m6A in both syn and anti conformation, which thus opens the way to the use of molecular simulations to investigate the effects of N6 methylations on RNA structural dynamics.

Fluorescent adenine analogues with ESPT characteristic utilized for real-time detecting DNA adduct

The 8-oxo-7,8-dihydro-2′-deoxyguanine (8-oxoG) is the representative damaged nucleoside that may increase the risk of developing diseases. Accordingly, the selective detection of 8-oxoG in DNA with minimal disturbance to the native structure is important to have an in-depth understanding of the formation mechanism and becomes an attractive tool for genomic research. To identify the DNA adduct in real-time efficiently, a series of quasi-intrinsic optical probes are performed based on the natural adenine, which has preference to form a stable base pair with 8-oxoG in the syn conformation. The calculations revealed that the A-analogues in solution could bring red-shifted absorption spectra and bright photoluminescence arisen from the additional π-conjugation by means of fluorophore modification and the ring expansion. Especially, A1 possesses large Stokes shifts and the highest fluorescence intensity in emission, which is proposed as the biosensor to monitor the optical changes in the presence and absence of the considered 8-oxoG. It is found that the fluorescence is insensitive to base pairing with thymine, while the excited state intermolecular proton transfer (ESPT) induced efficient fluorescence quenching is observed upon pairing with the 8-oxoG. To evaluate the direct usefulness of the bright adenine analogues in biological environment, we further examined the influences of linking deoxyribose on the absorption and emission, which are consistent with the experimental data.

Investigation of intramolecular hydrogen bonding in naphthoquinone derivatives by quantum chemical calculations

AbstractIntramolecular hydrogen‐bonded naphthoquinone derivatives are investigated using both DFT (density functional theory) and MP2 (Møller–Plesset perturbation theory) method. Three different sets of naphthoquinone derivatives, each set consisting of syn and anti conformers with respect to the substitution by (–OH/–NH2) at peri and para position of the ring, are considered for investigation. In all cases, the syn conformer is found to be energetically more stable compared with the anti conformer. However, the hydrogen bond strength of the anti conformer is found to be more as obtained from NBO (natural bond orbital) analysis and QTAIM (quantum theory of atoms in molecules) theory. The O···H–O interactions are associated with covalent character while O···H–N interactions are noncovalent in nature. The NCI (noncovalent interaction) isosurface clearly indicates the formation of O···H–O and O···H–N intramolecular hydrogen bond. The energy partition analysis indicates electrostatic interaction as the dominant force in stabilizing these systems. The aromaticity calculation by HOMA (harmonic oscillator model of aromaticity) index and Bird index indicate the syn conformer with higher aromaticity compared to the anti conformer. The overall stability of the syn conformers is thus dominated by the aromatic stabilization energy instead of hydrogen bonding energy. The global reactivity descriptors further support the higher stability of the syn conformers according to maximum hardness principle (MHP) and minimum electrophilicity principle (MEP).

Determination of Amide cis/trans Isomers in N-Acetyl-d-glucosamine: Tailored NMR Analysis of the N-Acetyl Group Conformation.

N‐Acetyl‐d‐glucosamine (GlcNAc) is one of the most common amino sugars in nature, but the conformation of its N‐acetyl group has drawn little attention. We report herein the first identification of NH protons of the amide cis forms of α‐ and β‐GlcNAc by NMR spectroscopy. Relative quantification and thermodynamic analysis of both cis and trans forms was carried out in aqueous solution. The NH protons were further utilized by adapting protein NMR experiments to measure eight J‐couplings within the N‐acetyl group, of which six are sensitive to the H2‐NH conformation and two are sensitive to the amide conformation. For amide cis and trans forms, the orientation between H2 and NH was determined as anti conformation, while a small percentage of syn conformation was predicted for the amide trans form of β‐GlcNAc. This approach holds great promise for the detailed conformational analysis of GlcNAc in larger biomolecules, such as glycoproteins and polysaccharides.

Stereoselective Cyclopropanation of 1,1-Diborylalkenes via Palladium-Catalyzed (Trimethylsilyl)diazomethane Insertion.

Palladium catalyzes the cyclopropanation of 2-substituted 1,1-diborylalkenes with (trimethylsilyl)diazomethane. The relative stereoselectivity is controlled via a carbene insertion sequence generating an exclusive anti conformation between the R and SiMe3 substituents. Mixed 1,1-diborylalkenes also contributed to the formation of stereoselective B, B, Si-cyclopropanes. Orthogonal activation with NaOtBu gives protodeborylation preferentially on the boron moiety syn to the aryl group. Further oxidation gives access to polyfunctional cyclopropyl alcohols with controlled enantioselectivity when chiral boryl motifs are involved.

Precursors of fatty alcohols in the ISM: Discovery of n-propanol

Context. Theories of the origins of life propose that early cell membranes were synthesised from amphiphilic molecules simpler than phospholipids, such as fatty alcohols. The discovery in the interstellar medium (ISM) of ethanolamine, the simplest phospholipid head group, raises the question whether simple amphiphilic molecules are also synthesised in space. Aims. We investigate whether precursors of fatty alcohols are present in the ISM. Methods. To do this, we have carried out a spectral survey at 7, 3, 2 and 1 mm towards the Giant Molecular Cloud G+0.693-0.027 located in the Galactic centre using the IRAM 30 m and Yebes 40 m telescopes. Results. Here, we report the detection in the ISM of the primary alcohol n-propanol (in both conformers Ga-n-C3H7OH and Aa-n-C3H7OH), a precursor of fatty alcohols. The derived column densities of n-propanol are (5.5 ± 0.4) × 1013 cm−2 for the Ga conformer and (3.4 ± 0.3) × 1013 cm−2 for the Aa conformer, which imply molecular abundances of (4.1 ± 0.3) × 10−10 for Ga-n-C3H7OH and of (2.5 ± 0.2) × 10−10 for Aa-n-C3H7OH. We also searched for the AGa conformer of n-butanol [AGa-n-C4H9OH] without success, yielding an upper limit to its abundance of ≤4.1 × 10−11. The inferred CH3OH:C2H5OH:C3H7OH:C4H9OH abundance ratios are 1:0.04:0.006:≤0.0004 towards G+0.693-0.027, that is, they decrease roughly by one order of magnitude for increasing complexity. We also report the detection of both syn and anti conformers of vinyl alcohol, with column densities of (1.11 ± 0.08) × 1014 cm−2 and (1.3 ± 0.4) × 1013 cm−2, and abundances of (8.2 ± 0.6) × 10−10 and (9.6 ± 3.0) × 10−11, respectively. Conclusions. The detection of n-propanol, together with the recent discovery of ethanolamine in the ISM, opens the possibility that precursors of lipids according to theories of the origin of life, could have been brought to Earth from outer space.

Synthesis, characterization and gas phase conformational properties of chlorodifluoroacetylsulfenyl chloride, CF2ClC(O)SCl

The simple chlorodifluoroacetylsulfenyl chloride species, CF2ClC(O)SCl, has been synthetized for the first time by the reaction between chlorodifluorothioacetic acid, CF2ClC(O)SH, and elemental chlorine. This sulfenyl carbonyl derivative has been exhaustively characterized by multinuclear (19F and 13C) NMR, FTIR, and FT-Raman spectroscopies. Conformational properties were investigated using gas-phase infrared and liquid Raman spectroscopy techniques, in combination with quantum chemical calculations at the B3LYP/6-311+G(3df) level of approximation. The coexistence of two forms, characterized by two orientations (gauche and syn) of the C-Cl single bond of the –CF2Cl group with respect to the C=O double bond, is confirmed in the gas phase. The synperiplanar (syn) conformation in the sulfenylcarbonyl chloride moiety is characterized by the C=O double bond and the S-Cl single bond adopting a mutual synperiplanar orientation. The lowest energy conformation is the gauche-syn, with the second anti-syn form higher in energy by around 1.0 kcal/mol.

Two methyl internal rotations of 2-acetyl-4-methylthiophene explored by microwave spectroscopy and quantum chemistry

The microwave spectrum of 2-acetyl-4-methylthiophene (2A4MT) was recorded in the frequency range from 2 to 26.5 GHz using a molecular jet Fourier transform microwave spectrometer, revealing two conformers, syn and anti. Both methyl groups in the molecule, the acetyl methyl and the ring methyl groups, undergo internal rotation, causing resolvable splittings of all rotational transitions into quintets. The torsional barriers determined for the acetyl methyl and the ring methyl rotors are 324.919(94) cm−1 and 210.7181(61) cm−1 for the syn conformer; the respective values for anti-2A4MT are 281.201(17) cm−1 and 212.9797(41) cm−1. The experimentally deduced rotational constants and torsional barriers are compared to values obtained from quantum chemical calculations. The barriers to methyl internal rotation are also compared to those of related molecules in order to establish a “thiophene class” concerning the acetyl methyl torsion.

Synthesis and DFT conformational analysis of trimethyl-functionalized [2.2]metacyclophanes and their Lewis-acid assisted reactions

The synthesis of the strained trimethyled anti-[2.2]metacyclophanes 5a and 5b is reported. They were synthesized by ring contraction of the corresponding unstrained cyclic precursors 2,11-dithia[3.3]metacyclophane-2,2,11,11-tetraoxides, 4a and 4b by the vacuum-pyrolysis elimination of sulfur dioxide ("sulfone pyrolysis‘).Tetraoxides 4a and 4b were generated by the oxidation of their respective dithia[3.3]metacyclophane precursors 3a and 3b. The macrocyclic coupling reactions which formed 3a and 3b also produced both anti- and syn-conformational isomers which could be separated from their respective reaction mixtures and whose structures were confirmed by 1H-NMR spectroscopy. Single-crystal X-ray analyses confirmed the anti conformation of anti-3b in the solid state and that the corresponding oxidized tetraoxide, syn-4b adopts a syn conformation. The Lewis acid (TiCl4/AlCl3-MeNO2)-catalyzed reactions of anti-5b under various conditions led to transannular cyclization to afford tetrahydropyrene 7, pyrene derivative 8 and/or de-tert-butylated anti-5a. A DFT (Density Functional Theory) computational study was conducted to determine the stabilities of the different conformational isomers of the target compounds.