Puckering Amplitude Research Articles

Crystal structure of 4'-O-methylalpinumisoflavone at 90K

4′-O-Methylalpinumisoflavone crystals which hitherto had been difficult to crystallize for X-ray diffraction analyses have been obtained from a demethylated product of O, O-dimethylalpinumisoflavone. The structural and conformational features of the crystal measured at 90 K are reported and compared with previously reported work of O,O-dimethylalpinumisoflavone and 5-O-methyl-4′-O-(3-methyl-but-2-en-1-yl) alpinumisoflavone. Each of these compounds is characterized by a six membered ring that is further fused to a benzopyrone isoflavone moiety resulting in a tricyclic ring system. This six membered ring shows a half-chair conformation in all the molecules studied, with the ring in the title compound showing the least Cremer-Pople puckering amplitude Q and shorter inter and intramolecular contacts. (© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Structures and stabilities of sugar radical nucleotides

The structures and energies of forming C1′, C2′, C3′ and C4′ radicals in sugar, and C5′ radical in various nucleotides have been studied by ab initio and DFT methods. Among these radicals, the radical at C1 position of sugar forms at lower energy level, and the efficiency of generating this radical will be more than other radicals. The puckering of sugar in 2-deoxy adenosine 5-monophosphate and 2-deoxy thymidine 5-monophosphate after radical formation at C1 is significant, herein C2 endo is observed in C1′ sugar radical compared to the C3 endo structure in its non-radical counterpart. In the case of 2-deoxy guanosine 5-monophosphate and 2-deoxy cystidine 5-monophosphate, C2 endo structures in sugar are found and distinct flattening of C3 center occurs after radical formation. There are intramolecular hydrogen bonds in the non-radical and radical structures of 2-deoxy guanosine 5-monophosphate and 2-deoxy adenosine 5-monophosphate nucleotides. In addition, significant variation of puckering amplitudes and phase angles between non-radical and C1′ sugar radical are also found.

Synthesis and Structure of Novel Conformationally Constrained 1‘,2‘-Azetidine-Fused Bicyclic Pyrimidine Nucleosides: Their Incorporation into Oligo-DNAs and Thermal Stability of the Heteroduplexes

[structures: see text] The synthesis of novel 1',2'-aminomethylene bridged (6-aza-2-oxabicyclo[3.2.0]heptane) "azetidine" pyrimidine nucleosides and their transformations to the corresponding phosphoramidite building blocks (20, 39, and 42) for automated solid-phase oligonucleotide synthesis is reported. The novel bicyclonucleoside "azetidine" monomers were synthesized by two different strategies starting from the known sugar intermediate 6-O-benzyl-1,2:3,4-bis-O-isopropylidene-D-psicofuranose. Conformational analysis performed by molecular modeling (ab initio and MD simulations) and NMR showed that the azetidine-fused furanose sugar is locked in a North-East conformation with pseudorotational phase angle (P) in the range of 44.5-53.8 degrees and sugar puckering amplitude (phi(m)) of 29.3-32.6 degrees for the azetidine-modified T, U, C, and 5-Me-C nucleosides. Thermal denaturation studies of azetidine-modified oligo-DNA/RNA heteroduplexes show that the azetidine-fused nucleosides display improved binding affinities when compared to that of previously synthesized North-East sugar constrained oxetane fused analogues.

PROSIT, AN ONLINE SERVICE TO CALCULATE PSEUDOROTATIONAL PARAMETERS OF NUCLEOSIDES AND NUCLEOTIDES

The online service PROSIT (Pseudo-Rotational Online Service and Interactive Tool) is a free service available at http://cactus.nci.nih.gov/prosit/ that performs pseudorotational analysis of nucleosides(tides). PROSIT reads the 3D coordinates of nucleosides and returns the pseudorotational phase angle P, puckering amplitude νmax, and other related information. As examples, the sugar conformations in a parallel-stranded guanine tetraplex and a four-way Holliday junction are presented here.

Conformational and crystal packing differences in (+)‐7,8‐Di‐tert‐butoxy‐1‐ phenyloctahydro‐1H‐pyrrolo(1,2‐b)‐1H‐phospholo(2,3‐d)isoxazole 1‐oxide diastereoisomers

AbstractThe crystal and molecular structures of (1S,3aR,7S,8S,8aR,8bR)‐(+)‐7,8‐Di‐tert‐butoxy‐1‐ph‐ enyloctahydro‐1H‐pyrrolo(1,‐b)‐1H‐phospholo(2,‐ d)isoxazole 1‐oxide (III, hereafter) and (1R,3aS,7S, 8S,8aS,8bS)‐(+)‐7,8‐Di‐tert‐butoxy‐1‐phenyloctahyd‐ ro‐1H‐pyrrolo(1,2‐b)‐1H‐phospholo(2,3‐d)isoxazole 1‐ oxide (IV, hereafter) have been determined. III crystallizes in space group P212121, and IV in P21 one. The conformational analysis of the puckered heteroatom three‐ring system shows the conformation of noticeable distorted envelope with puckering amplitude Q2 = 0.397 Å, the intermediate conformation between twisted and envelope with Q2 = 0.353 Å, and half‐chair conformation with Q2 = 0.451 Å, for phospholane, oxazolidine, and pyrrolidine rings of III, respectively. Rings in molecule of IV adopt conformations of envelopes with Q2 = 0.381 Å, Q2 = 0.367 Å, and Q2 = 0.363 Å, respectively, for the rings as described above. The molecules of III are assembled by intermolecular weak hydrogen bonds to the one‐dimensional chain along x‐axis. The structure of IV is built‐up of weak intermolecular hydrogen bonds to form a two‐dimensional hydrogen bond network. The differences in conformation between compounds III and IV cause changes in hydrogen bonding pattern, because in molecule IV there is no hydrogen cavern filled with three hydrogen bond donors, and one weak hydrogen bond has not enough strength to force such an arrangement as it is in III. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:613–620, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20160

PROSIT: Pseudo‐Rotational Online Service and Interactive Tool, Applied to a Conformational Survey of Nucleosides and Nucleotides.

A Pseudo-Rotational Online Service and Interactive Tool (PROSIT) designed to perform complete pseudorotational analysis of nucleosides and nucleotides is described. This service is freely available at http://cactus.nci.nih.gov/prosit/. Files containing nucleosides/nucleotides or DNA/RNA segments, isolated or bound to other molecules (e.g., a protein) can be uploaded to be processed by PROSIT. The service outputs the pseudorotational phase angle P, puckering amplitude νmax, and other related information for each nucleoside/nucleotide detected. The service was implemented using the chemoinformatics toolkit CACTVS. PROSIT was used for a survey of nucleosides contained in the Cambridge Structural Database and nucleotides in high-resolution crystal structures from the Nucleic Acid Database. Special cases discussed include nucleosides having constrained sugar moieties with extreme puckering amplitudes, and several specific DNA/RNA helices and protein-bound DNA oligonucleotides (Dickerson-Drew dodecamer, RNA/DNA...

Trans,trans,trans-2,3,5,8-Tetrabromo-1,4-dihydroxy-1,2,3,4-tetrahydronaphthalene

The structure of the title compound, C10H8Br4O2, has been determined at room temperature. The ten-membered tetrahydronaphthalene ring system is nearly planar, with a total puckering amplitude QT of 0.386 (5) Å. The crystal structure is stabilized by short inter- and intramolecular hydrogen-bond contacts.

2-[6-(3-Chlorophenyl)-2,4-dioxoperhydropyrimidin-3-yl]ethyl morpholine-4-carbodithioate

In the title compound, C17H20ClN3O3S2, the hexa­hydro­pyrimidine ring is puckered, the total puckering amplitude QT being 0.41 (1) A. The morpholine ring displays orientational disorder. Molecules are linked in the crystal via N—H⋯O and C—H⋯O interactions to form infinite chains.

PROSIT: pseudo-rotational online service and interactive tool, applied to a conformational survey of nucleosides and nucleotides.

A Pseudo-Rotational Online Service and Interactive Tool (PROSIT) designed to perform complete pseudorotational analysis of nucleosides and nucleotides is described. This service is freely available at http://cactus.nci.nih.gov/prosit/. Files containing nucleosides/nucleotides or DNA/RNA segments, isolated or bound to other molecules (e.g., a protein) can be uploaded to be processed by PROSIT. The service outputs the pseudorotational phase angle P, puckering amplitude numax, and other related information for each nucleoside/nucleotide detected. The service was implemented using the chemoinformatics toolkit CACTVS. PROSIT was used for a survey of nucleosides contained in the Cambridge Structural Database and nucleotides in high-resolution crystal structures from the Nucleic Acid Database. Special cases discussed include nucleosides having constrained sugar moieties with extreme puckering amplitudes, and several specific DNA/RNA helices and protein-bound DNA oligonucleotides (Dickerson-Drew dodecamer, RNA/DNA hybrid viral polypurine tract, Z-DNA enantiomers, B-DNA containing (L)-alpha-threofuranosyl nucleotides, TATA-box binding protein/TATA-box complex, and DNA (cytosine C5)-methyltransferase complexed with an oligodeoxyribonucleotide containing transition state analogue 5,6-dihydro-5-azacytosine). When the puckering amplitude decreases to a small value, the sugar becomes increasingly planar, thus reducing the significance of the phase angle P. We introduce the term "central conformation" to describe this part of the pseudorotational hyperspace in contrast to the conventional north and south conformations.

Cis– trans isomerization and puckering of proline residue

We report here the results on N-acetyl- l-proline- N′-methylamide (Ac-Pro-NHMe) calculated at the HF/6-31+G(d) level with the conductor-like polarizable continuum model (CPCM) of self-consistent reaction field methods to investigate the changes of backbone and prolyl ring along the cis– trans isomerization of the prolyl peptide bond. From the potential energy surface, the barrier to ring flip from the down-puckered conformation to the up-puckered one is estimated to be 2.5 and 3.2 kcal/mol for trans and cis conformers of Ac-Pro-NHMe, respectively. In particular, the ring flip seems to be inaccessible in the intermediate regions between trans and cis conformations, because of higher barriers (∼13–19 kcal/mol) to rotation of the prolyl peptide bond. The torsion angles for backbone and prolyl ring vary largely around the transition states at ω′≈120° and −70° for the prolyl peptide bond. Three kinds of puckering amplitudes show the same trend of puckering along the cis– trans isomerization although their absolute values are different. In particular, trans and cis conformations have the almost same degree of puckering. The cis populations and barriers to rotation of the prolyl peptide bond for Ac-Pro-NHMe are increased with the increase of solvent polarity, which is mainly ascribed to the decreases of relative free energies for cis conformations and the increase of relative free energies for transition states.

Structural determination of carvone, a component of spearmint, by means of gas electron diffraction augmented by theoretical calculations

The molecular structure and conformation of carvone, a compound with a minty odor, were investigated by means of gas electron diffraction supported by theoretical calculations. Electron diffraction patterns were recorded by heating the nozzle up to 128 °C to obtain enough scattering intensity. The infrared spectrum was also measured by using an absorption cell with a path length of 10 m. The obtained molecular scattering intensities were analyzed with the aid of theoretical calculations and infrared spectroscopy. It was revealed that the experimental data are well reproduced by assuming that carvone consists of a mixture of three conformers that have the isopropenyl group in the equatorial position and mutually differ in the torsional angle around the single bond connecting the ring and the isopropenyl group. It was also found that the puckering amplitude of the ring of carvone is close to those of menthol and isomenthol, a minty compound and its nonminty isomer. The determined structural parameters ( r g and ∠ α ) of the most abundant conformer of carvone are as follows: 〈 r(C–C)〉=1.520(3) Å; 〈 r(CC)〉=1.360(5) Å; r(CO)=1.225(5) Å; 〈 r(C–H)〉=1.104(4)Å; 〈∠CC–C〉=121.1(5)°; 〈∠C–C–C〉=110.4(5)°; ∠C–CO–C=117.1(14)°; 〈∠C–C–H〉=111.1(13)°. Angle brackets denote average values and parenthesized values are the estimated limits of error (3 σ) referring to the last significant digit.

Deoxyadenosine sugar puckering pathway simulated by the stochastic difference equation algorithm

The conformational transition pathway of sugar puckering between the C2 ′-endo and C3 ′-endo conformations of deoxyadenosine (dA) is reported using the stochastic difference equation (SDE) algorithm, which approximates long-time pathways. The south pucker is favored over the north by 0.34 ± 0.2 kcal/mol, and the free energy barrier is about 2.2 ± 0.2 kcal/mol above the global minimum. The transition occurs through the east barrier, with significant decrease in puckering amplitude near the barrier. These results are consistent with prior studies on sugars in nucleic acids and indicate that the SDE has potential for large nucleic acid and nucleic acid/protein systems.

1-(2′,3′-Anhydro-5′-O-benzoyl-β-D-lyxofuransoyl)-5-fluorouracil

The crystal structure of the title compound, C16H13FN2O6, was determined in order to establish the relative stereochemistry between the nucleoside base and the epoxide ring oxy­gen. This analysis allowed us to establish that the relationship of these two groups is cis. The furan­ose ring adopts an envelope conformation in which the oxy­gen is displaced above the plane (°E). The pseudorotational phase angle (P) is 88.5° and the puckering amplitude (τm) is 29.8°. The conformation about the C4—C5 bond is gauche–trans (ap) and the nucleoside base adopts the anti orientation.

A conformationally locked analogue of the anti-HIV agent stavudine. An important correlation between pseudorotation and maximum amplitude.

The synthesis and biological evaluation of a bicyclo[3.1.0]hexene nucleoside designed as a conformational mimic of the anti-HIV agent stavudine (1, D4T) is described. The unsaturated methanocarbocyclic pseudosugar of N-MCD4T (2) was constructed from an iodo-substituted precursor by a DBU-catalyzed olefination reaction. Mitsunobu coupling with N(3)-benzoylthymine afforded the desired target after deprotection. Both D4T and N-MCD4T are in the North (N) hemisphere of the pseudorotational cycle but 70 degrees away from a perfect N (P = 0 degrees ) conformation toward the East and West hemispheres, respectively. Despite this large difference, the double bond reduces the puckering amplitude (nu(max)) of N-MCD4T to 6.81 degrees, and the superposition of both structures showed a RMS deviation of only 0.039 A. The combined structural analysis of P and nu(max) shows that while the value of P may differ substantially, the low nu(max) resolves the differences and becomes the dominant pseudorotational parameter. N-MCD4T is active against HIV-1 and HIV-2 in CEM, MT-2, and MT-4 cells, and while it is somewhat less potent than D4T, it also appears to be less toxic. The triphosphate (N-MCD4TTP) inhibits HIV reverse transcriptase with a 10-fold higher IC(50) than D4TTP. By virtue of its carbocyclic nature, N-MCD4T (2) is a more robust molecule stable to conditions that would cleave D4T.

The molecular structure of 1,1-dicyanocyclopentane from gas electron diffraction data and ab initio calculations

The molecular structure of 1,1-dicyanocyclopentane (DCCP) has been investigated by means of gas-phase electron diffraction and ab initio calculation. Although the electron diffraction data could be fairly good reproduced by a C s (envelope) model we found it more pertinent to apply a pseudorotation model to account for the dynamic and large amplitude motion in DCCP. Based on this model we analyzed the dependency of the ring geometric parameters and vibrational mean amplitudes on the phase angle φ. For a better elucidation of this distinct dependency we developed particular equations which describe the dependency of the distribution of the delocalized net charges throughout the ring on the phase angle φ. For the purpose of a more systematical study of the substituent effect exerted by the cyano group we also investigated the structure and conformational stability of monocyanocyclopentane (MCCP) by means of various quantum mechanical methods. The MP2 method in combination with the basis sets 6-311+G(2df,2pd), 6-311++G(d,p), and 6-31G(d,p) favors the axial conformer which is in contradiction to earlier results which were obtained from electron diffraction data [J. Mol. Struct., 116 (1984) 29]. Using the same basis sets but the DFT/B3PW91 method, however, leads to a more stable equatorial conformer. This striking behavior is discussed in this paper. The joint electron diffraction and ab initio study has led to the following r α structural parameters of DCCP: r(CN)=1.152(2) Å, r(C–C)=1.472(5) Å, average r(C–C) ring=1.549(3) Å, ∠(C 5–C 1–C 2)=103.6(26)°, ∠(NC–C–CN)=109.0(35)°, ∠(C–CN)=175.2(33)°, and ∠(H–C–H)=112.7(23)°. The puckering amplitude for the five-membered ring was determined to be q=0.434(45) Å. The quantum mechanical calculations were carried out by utilizing the Hartree–Fock, density functional B3PW91, and perturbation MP2 methods and applying the basis sets: 6-31G(d,p), 6-311G(df,pd), 6-311+G(d,p) and 6-311++(2df,2pd). In contrast to the Mulliken poulation analysis the natural population analysis provided clear evidence for the electronic interaction and bond conjugation within the geminally substituted cyano groups.

4-(2-Benzylamino-1-oxoethyl)-1,2,3,4-tetrahydro-6,7-dimethylquinoxalin-2-one

All interatomic distances in the title compound, C19H21N3O2, are normal. The heterocycle of the quinoxalinone system exhibits a half-chair conformation. The value of the total puckering amplitude QT is 0.391 (5) Å. The benzyl­amino­methyl part of the side branch is close to planar. This weighted-least-squares plane makes a dihedral angle of 67.45 (14)° with the quinoxalinone plane. In the structure, there are C—H⋯N and C—H⋯O intramolecular hydrogen bonds. The mol­ecules are held together by N—H⋯O intramolecular hydrogen bonds, resulting in a dimeric structure. The dimers are linked by weak C—H⋯O intermolecular hydrogen bonds, resulting in a three-dimensional layered hydrogen-bonded network.

Extension of the Karplus Relationship for NMR Spin−Spin Coupling Constants to Nonplanar Ring Systems: Pseudorotation of Cyclopentane

A new Karplus equation for pseudorotating five-membered rings is derived by expanding calculated NMR spin−spin coupling constants (SSCCs) J as a function J(q,φ) of the puckering amplitude q and the pseudorotational phase angle φ. The approach was tested for cyclopentane but is equally applicable to ribose sugars and other biochemically interesting five-membered rings. It is based on the calculation of the conformational potential V(q,φ), which in the case of cyclopentane was determined at the MBPT(2)/cc-pVTZ level of theory. Cyclopentane is a free pseudorotor (barriers ΔE and ΔH ≤ 0.01 kcal/mol) with a puckering amplitude q = 0.43 Å and a barrier to inversion ΔH = 5.1 kcal/mol, in perfect agreement with experimental data. The SSCCs of cyclopentane were calculated at MBPT(2)/cc-pVTZ geometries by use of coupled perturbed density functional theory (CP-DFT) with the B3LYP functional and a (9s,5p,1d/5s,1p)[6s,4p,1d/3s,1p] basis set. In addition, coupled-cluster singles and doubles (CCSD) calculations were carried out to verify the CP-DFT results. All geometrical parameters and the 10 SSCCs of cyclopentane are determined as functions of the phase angle φ and averaged to give 〈nJ〉 values that can be compared with experimental data. The following SSCCs (in hertz) were obtained at CP-DFT/B3LYP/[6s,4p,1d/3s,1p]: 〈1J(CC)〉 = 34.0; 〈1J(CH)〉 = 127.6, exp 128.2; 〈2J(CCC)〉 = 2.3, exp (+)2.8; 〈2J(CCH)〉 = −2.6, exp (−)3.0; 〈2J(HCH)〉 = −12.4, exp (−)12.4; 〈3J(CCCH)〉 = 3.9; 〈3J(HCCH, cis)〉 = 7.7, exp 7.7; 〈3J(HCCH, trans)〉 = 5.6, exp 6.3; 〈4J(HCCCH, cis)〉 = 0.1; 〈4J(HCCCH, trans)〉 = −0.6. Magnitude and trends in calculated SSCCs are dominated by the Fermi contact term [with the exception of 1J(CC)]. A new way of determining puckering amplitude and pseudorotational angle by a combination of measured and calculated SSCCs is presented.

Modeling furanose ring dynamics in DNA.

Determination of the conformational flexibility of the furanose ring is of vital importance in understanding the structure of DNA. In this work we have applied a model of furanose ring motion to the analysis of deuterium line shape data obtained from sugar rings in solid hydrated DNA. The model describes the angular trajectories of the atoms in the furanose ring in terms of pseudorotation puckering amplitude (q) and the pseudorotation puckering phase phi. Fixing q, the motion is thus treated as Brownian diffusion through an angular-dependent potential U(phi). We have simulated numerous line shapes varying the adjustable parameters, including the diffusion coefficient D, pseudorotation puckering amplitude q, and the form of the potential U(phi). We have used several forms of the potential, including equal double-well potentials, unequal double-well potentials, and a potential truncated to "second order" in the Fourier series. To date, we have obtained best simulations for both equilibrium and nonequilibrium (partially relaxed) solid-state deuterium NMR line shapes for the sample [2' '-2H]-2'-deoxycytidine at the position C3 (underlined) in the DNA sequence [d(CGCGAATTCGCG)]2, using a double-well potential with an equal barrier height of U(0) = 5.5k(B)T ( approximately 3.3 kcal/mol), a puckering amplitude of q = 0.4 A, and a diffusion coefficient characterizing the underlying stochastic jump rate D = 9.9 x 10(8) Hz. Then the rate of flux for the C-D bond over the barrier, i.e., the escape velocity or the overall rate of puckering between modes, was found to be 0.7 x 10(7) Hz.

Molecular structure and pseudorotational motion of bromocyclopentane as determined by gas-phase electron diffraction

The molecular structure and pseudorotational motion of bromocyclopentane has been studied at a nozzle temperature of 333K. A pseudorotational potential function of the form V(φ)=(V1/2)(1+cosφ)+(V2/2)(1+cos2φ), where φ is the phase angle, and V1=0.74(40)kcal/mol and V2=0.42(85)kcal/mol gave the best agreement with the experimental data. The conformer with cyclopentane adopting an envelope form with the bromine atom located in the axial position is more stable than the form with the bromine located in the equatorial site by 0.74(40)kcal/mol. The thermal averaged puckering amplitude, ρ, for the five-membered ring and the averaged C–C bond length were found to be 0.37(2) and 1.540(2)Å, respectively.

Conformational study of the tricyclic sesquiterpene β‐panasinsene aided by ab initio calculations and simulated 1H NMR parameters†

AbstractAb initio calculations of the tricyclic sesquiterpene β‐panasinsene (1) provided theoretical H—C—C—H dihedral angles that allowed us to predict the corresponding 1H–1H vicinal coupling constant values, using a generalized Karplus‐type equation. These values, together with the experimental 1H chemical shifts extracted from an HMQC spectrum, were used as the initial input data for the full spectral simulation of 1, which provided an excellent correlation with the experimental 1H NMR spectrum after a few iterations. The complete assignment of the 1H NMR parameters allowed us to determine the conformation of 1 in solution. The four‐membered ring exists in a more flattened conformation than cyclobutane, with torsion angles of ∼12°. The five‐membered ring possesses a half‐chair conformation with pseudorotational parameters θm = 39.5° and P = 3.8°, while the six‐membered ring exists in a conformation close to the canonical chair, with angular variables θ = 9.2° and P2 = 15.5°, and the total puckering amplitude Q = 54.5°. Application of this procedure to β‐panasinsen‐5α‐ol (2) and β‐panasinsen‐5‐one (3) gave similar results. Copyright © 2001 John Wiley & Sons, Ltd.