Changes In Conformational Preferences Research Articles

Acid/Base-Triggered Photophysical and Chiroptical Switching in a Series of Helicenoid Compounds.

A series of molecules that possess two quinolines, benzoquinolines, or phenanthrolines connected in a chiral fashion by a biaryl junction along with their water-soluble derivatives was developed and characterized. The influence of the structure on the basicity of the nitrogen atoms in two heterocycles was examined and the photophysical and chiroptical switching activity of the compounds upon protonation was studied both experimentally and computationally. The results demonstrated that changes in the electronic structure of the protonated vs. neutral species, promoting a bathochromic shift of dominant electronic transitions and alternation of their character from π-to-π* to charge-transfer-type, when additionally accompanied by the high structural flexibility of a system, leading to changes in conformational preferences upon proton binding, produce particularly pronounced modifications of the spectral properties in acidic medium. The latter combined with reversibility of the read-out make some of the molecules in this series very promising multifunctional pH probes.

Refoldable Foldamers: Global Conformational Switching by Deletion or Insertion of a Single Hydrogen Bond

AbstractSmall changes in the structure of a foldamer may lead to gross changes in conformational preference. We show that the simple insertion or deletion of a single hydrogen bond by changes in pH or by photochemical deprotection is sufficient to refold a helical oligomer, interconverting M and P screw‐sense preference. As a consequence of the switch, information may be transmitted to a remote catalytic site, selectively directing the formation of either of two enantiomeric products by a reaction involving 1,22‐remote intermolecular asymmetric induction.

Refoldable Foldamers: Global Conformational Switching by Deletion or Insertion of a Single Hydrogen Bond.

Small changes in the structure of a foldamer may lead to gross changes in conformational preference. We show that the simple insertion or deletion of a single hydrogen bond by changes in pH or by photochemical deprotection is sufficient to refold a helical oligomer, interconverting M and P screw‐sense preference. As a consequence of the switch, information may be transmitted to a remote catalytic site, selectively directing the formation of either of two enantiomeric products by a reaction involving 1,22‐remote intermolecular asymmetric induction.

Conformational preferences of N‐methoxycarbonyl proline dipeptide

The conformational study on N-methoxycarbonyl-L-proline-N'-methylamide (Moc-Pro-NHMe, prolylcarbamate) is carried out using ab initio HF and density functional B3LYP methods with the self-consistent reaction field method in the gas phase and in solution (chloroform, acetonitrile, and water). The replacement of the N-acetyl group by the N-methoxycarbonyl group results in the changes in conformational preferences, populations for backbone and prolyl puckering, and barriers to cis-trans isomerization of the prolyl residue in the gas phase and in solution, although there are small changes in the geometry of the prolyl peptide bond and the torsion angles of backbone and prolyl ring. The cis population increases with the increase of solvent polarity, as found for Ac-Pro-NHMe (prolylamide), but it is amplified by 9% in the gas phase and about 17% in solution for prolylcarbamate compared with those for prolylamide. It is found that the cis-trans isomerization for prolylcarbamate proceeds through the clockwise rotation with omega' approximately +120 degrees about the prolyl peptide bond in the gas phase and in solution, as found for prolylamide. However, the rotational barriers to the cis-trans isomerization for prolylcarbamate are calculated to be 3.7-4.7 kcal/mol lower than those of prolylamide in the gas phase and in solution, and are found to be less sensitive to the solvent polarity. The calculated rotational barriers for prolylcarbamate in chloroform and water are in good agreement with the observed values. The shorter hydrogen-bond distance between the prolyl nitrogen and the amide H (H(NHMe)) of the NHMe group, the decrease in electron overlap of the prolyl C-N bond, and the favorable electrostatic interaction between the ester oxygen and the amide H(NHMe) for the transition state seem to play a role in lowering the rotational barrier of prolylcarbamate. The smaller molecular dipole moments of the ground- and transition-state structures for prolylcarbamate in the gas phase and in solution seem to be one of factors to make the rotational barrier less sensitive to the solvent polarity. As the solvent polarity increases (i.e., from the gas phase to chloroform to acetonitrile), the value of DeltaH(tc)(double dagger) decreases and the magnitude of DeltaS(tc)(double dagger) increases for prolylcarbamate, which results in a nearly constant value of the rotational barrier.

The Preference of Tryptophan for Membrane Interfaces: INSIGHTS FROM N-METHYLATION OF TRYPTOPHANS IN GRAMICIDIN CHANNELS

To better understand the structural and functional roles of tryptophan at the membrane/water interface in membrane proteins, we examined the structural and functional consequences of Trp --> 1-methyl-tryptophan substitutions in membrane-spanning gramicidin A channels. Gramicidin A channels are miniproteins that are anchored to the interface by four Trps near the C terminus of each subunit in a membrane-spanning dimer. We masked the hydrogen bonding ability of individual or multiple Trps by 1-methylation of the indole ring and examined the structural and functional changes using circular dichroism spectroscopy, size exclusion chromatography, solid state (2)H NMR spectroscopy, and single channel analysis. N-Methylation causes distinct changes in the subunit conformational preference, channel-forming propensity, single channel conductance and lifetime, and average indole ring orientations within the membrane-spanning channels. The extent of the local ring dynamic wobble does not increase, and may decrease slightly, when the indole NH is replaced by the non-hydrogen-bonding and more bulky and hydrophobic N-CH(3) group. The changes in conformational preference, which are associated with a shift in the distribution of the aromatic residues across the bilayer, are similar to those observed previously with Trp --> Phe substitutions. We conclude that indole N-H hydrogen bonding is of major importance for the folding of gramicidin channels. The changes in ion permeability, however, are quite different for Trp --> Phe and Trp --> 1-methyl-tryptophan substitutions, indicating that the indole dipole moment and perhaps also ring size and are important for ion permeation through these channels.

Probing Conformational Disorder in Neurotensin by Two-Dimensional Solid-State NMR and Comparison to Molecular Dynamics Simulations

An approach is introduced to characterize conformational ensembles of intrinsically unstructured peptides on the atomic level using two-dimensional solid-state NMR data and their combination with molecular dynamics simulations. For neurotensin, a peptide that binds with high affinity to a G-protein coupled receptor, this method permits the investigation of the changes in conformational preferences of a neurotransmitter transferred from a frozen aqueous solution via a lipid model phase to the receptor-bound form. The results speak against a conformational preorganization of the ligand in detergents in which the receptor has been shown to be functional. Further extensions to the study of protein folding are possible.

Differences in proton–proton coupling constants of N +–CH 2–CH 2 protons of some betaines, N +–(CH 2) 2-3–COO −, and their complexes in aqueous solution

Synthesis and 1H NMR spectra in D 2O of 4 betaines and 19 betaine complexes with mineral acids containing 2 or 3 CH 2 groups in the tether, N +–(CH 2) n –COO −, n=2,3, and diverse volume of the positively charged groups are reported. In compounds containing three CH 2 groups in the tether and three substituents at the nitrogen atom or α, α′-disubstituted pyridine ring, a characteristic multiplet for an AA′MM′X 2 spin system is observed. This is consistent with preference for trans conformation (68–85%). In the spectra of compounds with two CH 2 groups in the tether or three CH 2 groups and unsubstituted pyridine ring, the multiplet changes to a triplet and gives apparent A 2X 2 and A 2M 2X 2 spectra, respectively, consistent with no significant conformational preference. Both the number of CH 2 groups in tether and the bulkiness of the charged groups are responsible for the observed differences of N +CH 2 multiplicity and reflect changes in conformational preferences. According to the PM3 calculations, in the gas phase a gauche-like conformer is more stable than the trans, but in aqueous solution it is reverse.

Motion about the Csp2—S bond in thioanisole and some derivatives by the J method

Conformations about the Csp2—S bond in thioanisole and eight of its derivatives in solution are investigated by means of long-range spin–spin coupling constants over six bonds between the sidechain 13C nucleus and the para ring proton or 19F nucleus. According to geometry optimized STO 3G MO calculations the internal barrier to rotation is predominantly twofold in the gas phase in thioanisole and is 6.2 kJ/mol. In benzene solution the coupling constant yields 5.5(4) kJ/mol. Para fluorine and methyl substituents reduce the magnitude of the internal barrier, but meta methyl or chlorine substituents cause significant increases. In the presence of two ortho fluorine substituents the conformation of lowest energy has the C—S bond in a plane perpendicular to the aromatic plane, but die barrier may now contain a fourfold component. Addition of further fluorine substituents in the meta or para positions causes characteristic changes in conformational preferences of the thiomethyl group.

Influence of water on protein structure. An analysis of the preferences of amino acid residues for the inside or outside and for specific conformations in a protein molecule.

The x-ray structures of 20 proteins have been examined and each of the residues in these proteins was assigned to the inside or outside of the molecules and to a conformational state. The data obtained confirm that polar groups are generally found on the outside of proteins and nonpolar residues are generally found on the inside. Seven of the amino acids (Ala, Arg, Cys, His, Pro, Ser, Tyr) have inside/outside preferences which are not consistent with their usual assignment as either polar or nonpolar residues; explanations are given for these apparent inconsistencies. Of the three types of backbone structure considered here (extended, alpha helix, and nonregular), extended structures have the greatest preference for the inside of proteins, and nonregular structures have the greatest preference for the outside. It is suggested that differences in entropy play an important part in the inside/outside preferences of backbone structures. There are generally significant changes in the conformational preferences of the residues in going from the inside to the outside of proteins; environmental (rather than local) solute-solvent interactions seem to be the predominant cause of these changes in conformational preferences.