Rotamer Distribution Research Articles

Stereochemical and conformational features of ruthenium sulfoxide complexes: a molecular mechanics approach

Molecular mechanics force-field constants for ruthenium(II) sulfoxide complexes have been derived for the implementation of the AMBER force field. Stretching and bending constants were calculated by Badger’s and Halgren’s equations. Twenty-six parameters for sulfoxide, chlorine and metal atoms have been optimized to fit 836 experimental bond lengths and angles, using the Simplex method. Atomic charges have been calculated by the semiempirical method ZINDO/1. The goal was to rationalize the stereochemical and conformational features of this kind of metal complexes, through an accurate description of the molecular structures. The accuracy of the resulting geometries is reflected in the low values of the average differences between observed and calculated bond lengths and angles (-0.007 A and 0.0°) and their root-mean-square-deviations (0.017 A and 1.3°). Conformational analyses for S- and O-bonded sulfoxides have been carried out. Possible rotamer distributions for ruthenium(II)–dimethyl sulfoxide complexes containing lopsided nitrogen ligands, arising from hindered rotation about the Ru–N bonds, also have been investigated.

Analysis of Thermodynamic Determinants in Helix Propensities of Nonpolar Amino Acids through a Novel Free Energy Calculation

The relative helix propensities of Gly, Ala, Val, Ile, and Leu in the center of a polyalanine helix were calculated using a novel free energy simulation method (Wang et al. J. Mol. Biol. 1995, 253, 473) that permits the decomposition of the free energy into its various thermodynamic components. The calculated relative free energy changes agree well with the recent set of experimental data of Chakrabartty et al. (Protein Science 1994, 3, 843) on alanine-based peptides. The side chain rotamer distributions in the α-helix produced are also consistent with the reports in the literature based on a statistical survey of crystal structures of proteins. A detailed decomposition of the free energy showed that the solvation effect, or hydrophobicity in particular, has little contribution to the helix propensities of the amino acids relative to Gly. The side chain−helical matrix van der Waals interactions are generally favorable and account for a large part of the free energy change relative to Gly upon helix foldin...

Computer simulation of chiral liquid crystal phases. IV. Intermolecular chirality transfer to rotamers in a cholesteric phase

Abstract Intermolecular chirality transfer was studied by investigating the conformational distribution of rotamers in a cholesteric guest-host phase using Monte Carlo (MC) simulations in the NVT ensemble. The guest-host system under investigation was given by N c = 238 rigid, chiral Gay-Berne atropisomers as host molecules and N a = 18 flexible Gay-Berne rotamers as guest molecules. The rigid, chiral Gay-Berne atropisomers of point symmetry group D2 were defined by joining two Gay-Berne particles through a bond with a suitable fixed dihedral angle. The possibility of internal rotation about the bond axis without a rotational barrier was introduced as an internal degree of freedom for the guest molecules, for convenience denoted as Gay-Berne rotamers. Starting from an isotropic configuration, cholesteric phases were obtained on equilibrating the guest-host systems, whereby left-handed and right-handed cholesterics were formed depending on the M- and P-helicity of the atropisomers, respectively. Analysing ...

Heteronuclear Nucleobase Complexes as Tools for the Isolation of the Minor Rotamer of the Parent Compound: Synthesis and Crystal Structure Determination of Head-Head and Head-Tail Forms of trans-[(CH3NH2)2Pt(1-MeC-N3)2]2+ (1-MeC = 1-methylcytosine)

The two rotamers (head-tail, 1, and head-head, 2) of the bis(1-methylcytosine)complex of trans-(CH3NH2)2Pt(II), have been crystallized as ClO4- (1, 2a) and PF6- (2b) salts and characterized by X-ray crystal structure analysis and 1H and 195Pt NMR spectroscopy. In aqueous solution, 1 is preferred over 2 by 70:30. Upon slow crystallization from H2O, 1 is obtained as the only product. Isolation of 2a and 2b has now been accomplished via formation of the heteronuclear derivative trans-[(CH3NH2)2Pt(1-MeC--N3,N4)2Hg]2+, in which the deprotonated 1-methylcytosinato ligands (1-MeC-) are oriented head-head, precipitation of Hg(II) by thiourea, and rapid crystallization of the parent compound. The solid state structures of 1 and 2b differ markedly in a number of aspects. Isolation of pure 1 and 2 permits a detailed study of the kinetics and thermodynamics of the interconversion of the two rotamers. From comparison with the behavior of 1 and 2 in H2O on the one hand and DMSO and DMF on the other a clear solvent effect on the rotamer distribution is seen which most likely relates to differences in H bonding between solvent and solute.

Stereochemistry of the N-glycosylation sites in glycoproteins

The stereochemical features displayed by the N-glycosidic linkage in crystalline N-linked glycoproteins are analyzed. From the statistical analysis of 44 different glycosylation sites belonging to 26 glycoproteins of the Brookhaven Protein Data Bank, a mean standard geometry for the GlcNAc moiety, along with a rationalization of its conformational behavior, can be proposed. As for the glycopeptide linkage, the distribution of observed conformations has been analyzed on the basis of molecular mechanics calculations. The rotamer distribution of the Asn side chains conforms to that observed on non-glycosylated structures, and it agrees with the pattern of flexible conformations gathered from NMR measurements. In characterizing the protein-glycan interactions, some hydrogen bonds occur. Stacking between the amphiphilic moiety of the glycan and some surrounding aromatic, or at least hydrophobic, amino acid residues is also found. When looking at the secondary structure of the glycosylated peptide, only 25% of the glycosylation sites correspond to situations where Asn is located at the top of a beta-turn. Other types of secondary structure exist which fulfill the spatial requirement of having the glycan exposed at the surface of the protein. These data can be compared with the most recent studies on the peptide conformation which would be required for glycosylation.

The chemistry of peroxynitrite: a product from the reaction of nitric oxide with superoxide

Nitric oxide and superoxide, which are produced by several cell types, rapidly combine to form peroxynitrite. This reaction can result in nitric oxide scavenging, and thus mitigation of the biological effects of superoxide. Also, superoxide can trap and hence modulate the effects of nitric oxide; superoxide dismutase, by controlling superoxide levels, therefore can influence the reaction pathways open to nitric oxide. The production of peroxynitrite, however, causes its own sequelae of events: Although neither .NO nor superoxide is a strong oxidant, peroxynitrite is a potent and versatile oxidant that can attack a wide range of biological targets. The peroxynitrite anion is relatively stable, but its acid, peroxynitrous acid (HOONO), rearranges to form nitrate with a half-life of approximately 1 s at pH 7, 37 degrees C. HOONO exists as a Boltzmann distribution of rotamers; at 5-37 degrees C HOONO has an apparent acidity constant, pKa,app, of 6.8. Oxidation reactions of HOONO can involve two-electron processes (such as an SN2 displacement) or a one-electron transfer (ET) reaction in which the substrate is oxidized by one electron and peroxynitrite is reduced. These oxidation reactions could involve one of two mechanisms. The first mechanism is homolysis of HOONO to give HO. and .NO2, which initially are held together in a solvent cage. This caged pair of radicals (the "geminate" pair) can either diffuse apart, giving free radicals that can perform oxidations, or react together either to form nitrate or to reform HOONO (a process called cage return). A large amount of cage return can explain the small entropy of activation (Arrhenius A-factor) observed for the decomposition of HOONO. A cage mechanism also can explain the residual yield of nitrate that appears to be formed even in the presence of high concentrations of all of the scavengers studied to date, since scavengers capture only free HO. and .NO2 and not caged radicals. If the cage mechanism is correct, the rate of disappearance of peroxynitrite be slower in solvents of higher viscosity, and we do not find this to be the case. The second mechanism is that an activated isomer of peroxynitrous acid, HOONO*, can be formed in a steady state. The HOONO* mechanism can explain the inability of hydroxyl radical scavengers to completely block either nitrate formation or the oxidation of substrates such as methionine, since HOONO* would be less reactive, and therefore more selective, than the hydroxyl radical itself.(ABSTRACT TRUNCATED AT 400 WORDS)

Diastereoselective conversion of L-(S)-erythrulose to 2-amino-2-deoxy-L-erythritol

L-(S)-Erythrulose ( 1) was converted into 2-amino-2-deoxy-L-erythritol ( 2) (six steps, overall yield 35%) through diastereoselective reduction of the bridged orthoester 21, (1S,5S)-2,7,8-trioxabicyclo[3.2.1]octan-4-one- O-benzyloxime, with K-selectride® as the key process. Alternative methods, involving reduction of the imino group in acyclic O-benzyloxime derivatives of 1, or reductive amination of the 2-ketone function, afforded various proportions of erythro and threo 2-amino diastereoisomers. The distribution of rotamers for the deprotected ammonium salts apparently is governed by hydrogen bonding between the ammonium group and the 3-hydroxyl oxygen, resulting in characteristic 3 J H−2,H−3 coupling constant values. Substitution of the bridged O-benzyloximes 21 and 22 via deprotonation of the α-methylene position was not successful.

Evidence against the reactive rotamer explanation of the gem-dialkyl effect

Acceleration of intramolecular reaction rates with increasing substitution has been known for a long time. The most common explanation used for this phenomenon is the 'Reactive Rotamer Effect' which states that “The ring closure reaction proceeds at a greater rate on geminal (or alkyl) substitution because of the resultant decrease in unprofitable rotamer distribution”. 1 This research presents evidence against this explanation and suggests an alternate explanation for the cause of the gem-dialkyl effect.

α‐Helix‐forming propensities in peptides and proteins

Much effort has been invested in seeking to understand the thermodynamic basis of helix stability in both peptides and proteins. Recently, several groups have measured the helix-forming propensities of individual residues (Lyu, P.C., Liff, M.I., Marky, L.A., Kallenbach, N.R. Science 250:669-673, 1990; O'Neil, K.T., DeGrado, W.F. Science 250:646-651, 1990; Padmanabhan, S., Marqusee, S., Ridgeway, T., Laue, T.M., Baldwin, R.L. Nature (London) 344:268-270, 1990). Using Monte Carlo computer simulations, we tested the hypothesis that these differences in measured helix-forming propensity are due primarily to loss of side chain conformational entropy upon helix formation (Creamer, T.P., Rose, G.D. Proc. Natl. Acad. Sci. U.S.A. 89:5937-5941, 1992). Our previous study employed a rigid helix backbone, which is here generalized to a completely flexible helix model in order to ensure that earlier results were not a methodological artifact. Using this flexible model, side chain rotamer distributions and entropy losses are calculated and shown to agree with those obtained earlier. We note that the side chain conformational entropy calculated for Trp in our previous study was in error; a corrected value is presented. Extending earlier work, calculated entropy losses are found to correlate strongly with recent helix propensity scales derived from substitutions made within protein helices (Horovitz, A., Matthews, J.M., Fersht, A.R. J. Mol. Biol. 227:560-568, 1992; Blaber, M., Zhang, X.-J., Matthews, B.M. Science 260:1637-1640, 1993). In contrast, little correlation is found between these helix propensity scales and the accessible surface area buried upon formation of a model polyalanyl alpha-helix. Taken in sum, our results indicate that loss of side chain entropy is a major determinant of the helix-forming tendency of residues in both peptide and protein helices.

The conformation of 2-fluoroethanol — is intramolecular hydrogen bonding important?

The conformations of 2-fluoroethanol (FE) and trans-4-tert-butyl-cis-2-fluorocyclohexanol (1) have been investigated by FT-IR and 1H NMR spectroscopy and the methyl ether of 1 (3) by 13C NMR spectroscopy. The energies of the conformations of FE, its methyl ether, cis-2-fluorocyclohexanol (4) and its methyl ether (5) were investigated by molecular mechanics (MMPMI) calculations. FE and its methyl ether were investigated by ab initio calculations (MP2/6-31++G**//MP2/6-31++G**). The results were all consistent with a dominance (> 90%) of the gauche rotamer around the CH2CH2 fragment in FE. Furthermore, the gauche rotamer around the CH2OH bond of FE with the hydroxyl proton pointing towards the fluorine atom was also a major component making the conformation Gg′ the most important one. However, from the conformations of the methyl ethers 1-fluoro-2-methoxyethane and 3 it was concluded that an intramolecular hydrogen bond was not important for this dominance. Other interactions, e.g. the repulsive forces between the lone pair electrons of the oxygen atom and the fluorine atom, were found to be more important than a hydrogen bond for the conformational composition around the CO bond. The rotamer distribution around the CH2CH2 bond was found to be the result of the gauche effect.

NMR studies of some (1 → 6)-linked disaccharide methyl glycosides

NMR studies have been performed on the methyl glycosides of some (1 → 6)-linked disaccharides. Observed J 6,5 pro-R and J 5,6 pro-S values indicate that, for the 6-substituted d-gluco- and d-galacto-pyranosides, the rotamer distribution around the C-5C-6 bond deviates somewhat from that observed for the respective unsubstituted monosaccharide glycosides. There is also a difference between 6- O-α- d- or 6- O-β- l- on the one hand and 6- O-β- d- or 6- O-α- l-substituted glycosides on the other, with somewhat larger values for J 5,6 pro-R for the latter two indicating a higher proportion of the gauche-trans conformer. The glycosylation shifts observed for the signals from the 6-protons in the glycosidic linkage were dependent on the type of anomeric and absolute configuration of the glycosyl group. NOE measurements by irradiation of the anomeric proton indicated that sugars 6-substituted with α- d- or β- l-glycosyl groups have highly populated conformations in which H-1 and H-6 pro-S are proximal, and for β- d- and α- l-glycosyl groups conformations in which H-1 and H-6 pro-R are proximal.

Conformation analysis of 3'-fluorinated A(2'-5')A(2'-5')A fragments. Relation between conformation and biological activity.

A one- and two-dimensional NMR study has been performed on seven A(2'-5')A(2'-5')A fragments containing 9-(3'-fluoro-3'-deoxy-beta-D-xylofuranosyl)-adenine (AF) or 3'-fluoro-3'-deoxyadenosine (AF) residues at different positions, and on the corresponding monomers. A(2'-5')A(2'-5')A served as a reference compound. The fluoro substituent governs the conformation of the sugar ring: an AF residue displays mainly N-type sugar and the ring is considerably flattened (phi N approximately 30 degrees) compared to AF residues (phi S approximately 40 degrees), which exhibit almost pure S-type conformation. Moreover, in AF moieties the rotamer distribution around torsion angle gamma (O5'-C5'-C4'-C3') and the base orientation are influenced to a large extent by the presence of the fluorine substituent. The sugar rings of nonfluorinated residues in the trimers appear rather flexible. A possible correlation between the conformational characteristics of the fluorinated fragments and their biological activity has been found: the fragments that meet the prerequisites for binding to RNase L indeed show enhanced binding to this endonuclease. Furthermore, substitution of the 3'-OH group of the second residue by hydrogen or of the 3'-OH group of the 2'-terminal residue by fluorine or hydrogen results in increased resistance towards 2'-5'-phosphodiesterase.

Conformational analysis of the carbohydrate portion of T and T N haptens by NMR spectroscopy and molecular modeling

The conformations of the crotyl derivatives of the T (β-D-Gal(1→3)-Crotylα-D-GalNAc) and T N (Crotylα-D-GalNAc) haptens as well as of Meβ-D-Gal were investigated in D 2O, DMSO-d 6 and 85% H 2O: 15% acetone-d 6 using 1H and 13C NMR spectroscope and molecular modeling. The two sugar moieties are in a 4C 1 conformation and they adopt a quasi-parallel orientation in the T hapten, with hydrogens H1′ and H3 being in close proximity. The hydroxymethyl chains adopt a gt conformation, the NH and H2 are antiperiplanar whereas the crotyl chain displays significant segmental mobility. Vicinal coupling constants of hydroxyl protons and saturation transfer rates in aqueous media indicate that the hydroxyl groups are relatively mobile except for OH2′ which probably forms a weak hydrogen bond with the amide nitrogen. An energy-minimized molecular model consistent with all the NMR data could be constructed and areas favorable to hydrophilic interactions could be determined. Except for the rotamer distribution of the hydroxymethyl group, the conformations are very similar in all three solvents.

An NMR and conformational investigation of the trans-syn cyclobutane photodimers of dTpdU.

Two trans-syn cyclobutane photodimers of thymidylyl (3'-5') deoxyuridine were formed by deamination of the corresponding trans-syn cyclobutane photodimers of thymidylyl (3'-5') deoxycytidine and were examined by 1H-, 13C-, and 31P-nmr spectroscopy. Correlation spectroscopy, nuclear Overhauser enhancement spectroscopy, and one-dimensional heterodecoupling experiments allowed a more complete assignment of the 1H spectra, compared with previous reports by Koning et al. [(1991) European Journal of Biochemistry, Vol. 195, pp. 29-40] and Liu and Yang [(1978) Biochemistry, Vol. 17, pp. 4865-4876]. Deoxyribose ring conformations were calculated from 1H coupling constants by pseudorotational analysis, and rotamer distributions of exocyclic bonds were calculated from the observed homonuclear and heteronuclear coupling constants. The cyclobutane ring configuration (CB) of each isomer was identified, using arguments based upon observed scalar and dipolar couplings. Glycosidic bond conformation was ascertained from nuclear Overhauser enhancements observed between base and deoxyribose protons. Isomer I (S-type class; CB-; SYN-ANTI) and isomer II (N-type class; CB+; ANTI-SYN) exhibit markedly different conformational features. 31P chemical shifts and exocyclic bond rotamer distributions indicate diminished backbone flexibility for both photoproducts relative to parent thymidylyl (3'-5') deoxyuridine. Isomer I (SYN-ANTI) is particularly rigid, while isomer II (ANTI-SYN) maintains some flexibility. Also, 13C spectra were acquired and assigned unequivocally with the aid of short- and long-range two-dimensional heteronuclear shift correlation experiments.

Modeling carbohydrate conformations from NMR data: maximum entropy rotameric distribution about the C5-C6 bond in gentiobiose

The conformation about the C5-C6 bond in β-gentiobiose, (β-D-Glcp-(1→6)-β-D-Glcp), has been analyzed in terms of the maximum entropy probability density distribution of the dihedral angle Ω. This analysis used the information carried by proton-proton and carbon-proton vicinal coupling constants and proton-proton cross-relaxation rates. Two major conformations characterized by Ω=-68.9 o ±6.3 o and Ω=79.0 o ±3.4 o were found with populations of 0.34±0.06 and 0.66±0.06, respectively

Diastereomer differentiation during 1,2-addition of Grignard reagents under rotamer distribution control

Construction of ( R)-tertiary alcohols through diastereofacial differentiation under rotamer distribution control was accomplished with complete selectivity by means of simple nucleophilic addition of Grignard reagents to chiral α-ketoamides elaborated from C 2-symmetrical imides and the absolute configuration was established by an X-ray crystallographic analysis.

Synthesis and stereochemistry of Reissert compounds from benzothiazole

Benzothiazole (3-aroyl-2-cyano-2,3-dihydro) 1-5, Reissert compounds, were synthesized, characterized and alkylated to produce benzothiazole (2-alkyl-3-aroyl-2-cyano-2,3-dihydro) 6-9. Conformational analysis of 2 by the use of high resolution (400 MHz) variable temperature NMR spectroscopy indicated that the Z to E amide conformer ratio is 79:21 (±3%) in CDCl 3 at 213 K (-60 o C) and 57:43 (±3%) in C 6 D 5 CD 3 at 213 K. Aromatic solvent induced shifts were employed to determine the distribution of rotamers and indicated that the alkylated benzothiazole Reissert compound 8 existed in only the Z amide conformation. Hindered aryl-carbonyl rotation was also detected in the Reissert compounds

The "CUPID" method for calculating the continuous probability distribution of rotamers from NMR data. [Erratum to document cited in CA117(4):34037s

The "CUPID" method for calculating the continuous probability distribution of rotamers from NMR data. [Erratum to document cited in CA117(4):34037s

The "CUPID" method for calculating the continuous probability distribution of rotamers from NMR data

We present a new method, ContinUous ProbabIlity Distribution of rotamers (CUPID), for determining the distribution of rotamer probability p(X) about a dihedral angle χ. This method utilizes measured vicinal homonuclear and heteronuclear spin-spin coupling constants (J) and nuclear Overhauser enhancements (NOEs) from NMR spectra and demands no prior assumption about the conformations or the degree of flexibility across the bond

Maximum Entropy Rotameric Distribution of Ethoxybenzene Dissolved in Liquid Crystals

Abstract The analysis of interproton dipolar couplings derived by 1H-NMR spectra of molecules dissolved in partially oriented nematic solvents (LX-NMR) is a powerful tool for accurate structure determination in liquid phase. A characterization of the distribution of the internal variables in non-rigid molecules has been one of the central goals of LX-NMR. This kind of study appears particularly relevant when considering that the mesogens themselves are often composed of molecules with one or several internal degrees of freedom. The application of the principle of Maximum Entropy (ME) has been shown able to give the least biased rotameric distribution for one internal degree of freedom. This method is now extended to the problem of two internal rotations and applied to analyse the dipolar couplings of ethoxybenzene. A bidimensional probability distribution is thus obtained, that is in agreement with preliminary findings of a ab initio calculation on the molecule.