Stereochemistry of peptides containing 1-aminocyclopentane carboxylic acid (Acc5). Solution and solid state conformations of Boc-Acc5-Acc5-NHMe.

The conformational analysis of a protected homodipeptide of 1-aminocyclopentanecarboxylic acid (Acc5) has been carried out. 1H-nmr studies establish a ?-turn conformation for Boc-Acc5-Acc5-NHMe in chloroform and dimethylsulfoxide solutions involving the methylamide NH in an intramolecular hydrogen bond. Supportive evidence for the formation of an intramolecular hydrogen bond is obtained from ir studies. X-ray diffraction studies reveal a type III ?-turn conformation in the solid state stabilized by a 4 ? 1 hydrogen bond between the Boc CO and methylamide NH groups. The ?,? values for both Acc5 residues are close to those expected for an ideal 310-helical conformation (?? ± 60°, ?? ±30°).

b-Turn conformations in crystal structures of model peptides containing a,a-di-n-propylglycine (Dpg) and a,a-di-n-butyl-glycine (Dbg).

The crystal state conformations of three peptides containing the a,a-dialkylated residues, a,adi n-propylglycine (Dpg) and a,@-di-n-butylglycine (Dbg), have been established by x-ray diffraction. Boc-Ala-Dpg-Ala-OMe ( I ) and Boc-Ala-Dbg-Ala-OMe (III) adopt distorted type II @-turn conformations with Ala ( I ) and Dpg/Dbg (2) as the corner residues. In both peptides the conformational angles at the Dxg residue (I: 4 = 66.23 J/ = 19.3'; III: 4 = 66S0, J. = 21 .la)deviate appreciablyfrom ideal values for the i + 2 residue in a type II @-turn. In both peptides the observed(N. 0) distances between the Boc CO andAla(3) NHgroups are far too long (I:3.44 k; III: 3.63 k) for an intramolecular 4 + 1 hydrogen bond. Boc-Ala-Dpg-Ala-NHMe (II)crystallizes with two independent molecules in the asymmetric unit. Both molecules IIA and IIB adopt consecutive @-turn (type III-III in IIA and type III-I in IIB) or incipient 3,,,-helical structures, stabilized by two intramolecular 4 --t I hydrogen bonds. In all four molecules the bond angle N-C"-C' ( T ) at the Dxg residues are 2 1109 The observation of conformational angles in the helical region of 4,J/ space at these residues is consistent with theoretical predictions

A nonhelical, multiple β-turn conformation in a glycine-rich heptapeptide fragment of trichogin A IV containing a single central α-aminoisobutyric acid residue

The conformational properties of the protected seven-residue C-terminal fragment the lipopeptaibol antibiotic Trichogin A IV (Boc-Gly-Gly-Leu-Aib-Gly-Ile-Leu-OMe) has been examined in CDCl3 and (CD3)2SO by 1H-nmr. Evidence for a multiple β-turn conformation [type I′ at Gly(1)-Gly(2), type II at Leu(3)-Aib(4), and a type I′ at Aib(4)-Gly(5)] suggests that Leu(3) has preferred an extended or semiextended conformation over a helical conformation in CDCl3. This structure is thus in contrast to earlier observations of seven-residue peptides containing a single central Aib preferring helical conformations in both solution and crystalline slates. A structural transition to a frayed right-handed helix is absented in (CD3)2SO. These results suggest that nonhelical conformations may be important in Gly-rich peptides containing Aib. Further, the presence of amino acids with contradictory influences on backbone conformational freedom can lead to well-defined conformational transitions even in small peptides

Conformational Polymorphism in Telomeric Structures: Loop Orientation and Interloop Pairing in d(G4TnG4),

Sequence repeats constituting the telomeric regions of chromosomes are known to adopt a variety of unusual structures, consisting of a G tetraplex stem and short stretches of thymines or thymines and adenines forming loops over the stem. Detailed model building and molecular mechanics studies have been carried out for these telomeric sequences to elucidate different types of loop orientations and possible conformations of thymines in the loop. The model building studies indicate that a minimum of two thymines have to be interspersed between guanine stretches to form folded-back structures with loops across adjacent strands in a G tetraplex (both over the small as well as large groove), while the minimum number of thymines required to build a loop across the diagonal strands in a G tetraplex is three. For two repeat sequences, these hairpins, resulting from different types of folding, can dimerize in three distinct ways-i.e., with loops across adjacent strands and on same side, with loops across adjacent strands and on opposite sides, and with loops across diagonal strands and on opposite sides-to form hairpin dimer structures. Energy minimization studies indicate that all possible hairpin dimers have very similar total energy values, though different structures are stabilized by different types of interactions. When the two loops are on the same side, in the hairpin dimer structures of d(G(4)T(n)G(4)), the thymines form favorably stacked tetrads in the loop region and there is interloop hydrogen bonding involving two hydrogen bonds for each thymine-thymine pair. Our molecular mechanics calculations on various folded-back as well as parallel tetraplex structures of these telomeric sequences provide a theoretical rationale for the experimentally observed feature that the presence of intervening thymine stretches stabilizes folded-back structures, while isolated stretches of guanines adopt a parallel tetraplex structure

Hybrid Polypeptides: Gabapentin as a Stereochemically Constrained gamma-Amino Acid Residue

The design of folded structures in peptides containing the higher homologues of alpha-amino acid residues requires the restriction of the range of local conformational choices In alpha-amino acids stereochemically constrained residues like alpha,alpha-dialkylated residue, aminoisobutyric acid (Aib), and D-Proline ((D)Pro) have proved extremely useful in the design of helices and hairpins in short peptides Extending this approach, backbone substitution and cyclization are anticipated to bc useful in generating conformationally constrained beta- and gamma-residues This brief review provides a survey of work on hybrid peptide sequences concerning the conformationally constrained gamma-amino acid residue 1-aminomethyl cyclohexane acetic acid, gabapentin (Gpn) This achiral, beta,beta-disubstituted, gamma-residue strongly favors gauche-gauche conformations about the C-alpha-C-beta (0(2)) and C-alpha-C-gamma (0(1)) bonds, facilitating local folding The Gpn residue can adopt both C-7 (NH1 -> CO1) and C-9 (CO1 (I)<- NH1+I) hydrogen bonds which are analogous to the C-5 and C7 (gamma-turn) conformations at alpha-residues In conjunction with adjacent residues, Gpn may be used in ay and gamma alpha segments to generate C-12 hydrogen bonded conformations which may be considered as expanded analogs of conventional beta-turns The structural characterization of C-12 helices, C-12/C-10 helices with mixed hydrogen bond directionalities and beta-hairpins incorporating Gpn residues at the turn segment is illustrated (C) 2010 Wiley Periodicals, Inc Biopolymers (Pept Sci) 94 733-741 2010

Investigating Diproline Segments in Proteins: Occurrences, Conformation and Classification

The covalent linkage between the side-chain and the backbone nitrogen atom of proline leads to the formation of the five-membered pyrrolidine ring and hence restriction of the backbone torsional angle phi to values of -60 degrees +/- 30 degrees for the L-proline. Diproline segments constitute a chain fragment with considerably reduced conformational choices. In the current study, the conformational states for the diproline segment ((L)Pro-(L)Pro) found in proteins has been investigated with an emphasis on the cis and trans states for the Pro-Pro peptide bond. The occurrence of diproline segments in turns and other secondary structures has been studied and compared to that of Xaa-Pro-Yaa segments in proteins which gives us a better understanding on the restriction imposed on other residues by the diproline segment and the single proline residue. The study indicates that P(II)-P(II) and P(II)-alpha are the most favorable conformational states for the diproline segment. The analysis on Xaa-Pro-Yaa sequences reveals that the XaaPro peptide bond exists preferably as the trans conformer rather than the cis conformer. The present study may lead to a better understanding of the behavior of proline occurring in diproline segments which can facilitate various designed diproline-based synthetic templates for biological and structural studies. (C) 2011 Wiley Periodicals, Inc. Biopolymers 97: 54-64, 2012.

Chain Length Effects on Helix-Hairpin Distribution in Short Peptides with Aib-(D)Ala and Aib-Aib Segments

The Aib-(D)Ala dipeptide segment has a tendency to form both type-I'/III' and type-I/III beta-turns. The occurrence of prime turns facilitates the formation of beta-hairpin conformations, while type-I/III turns can nucleate helix formation. The octapeptide Boc-Leu-Phe-Val-Aib-(D)Ala-Leu-Phe-Val-OMe (1) has been previously shown to form a beta-hairpin in the crystalline state and in solution. The effects of sequence truncation have been examined using the model peptides Boc-Phe-Val-Aib-Xxx-Leu-Phe-NHMe (2, 6), Boc-Val-Aib-Xxx-Leu-NHMe (3, 7), and Boc-Aib-Xxx-NHMe (4, 8), where Xxx = (D)Ala, Aib. For peptides with central Aib-Aib segments, Boc-Phe-Val-Aib-Aib-Leu-Phe-NHMe (6), Boc-Val-Aib-Aib-Leu-NHMe (7), and Boc-Aib-Aib-NHMe (8) helical conformations have been established by NMR studies in both hydrogen bonding (CD(3)OH) and non-hydrogen bonding (CDCl(3)) solvents. In contrast, the corresponding hexapeptide Boc-Phe-Val-Aib-(D)Ala-Leu-Phe-Val-NHMe (2) favors helical conformations in CDCl(3) and beta-hairpin conformations in CD(3)OH. The beta-turn conformations (type-I'/III) stabilized by intramolecular 4 -> 1 hydrogen bonds are observed for the peptide Boc-Aib-(D)Ala-NHMe (4) and Boc-Aib-Aib-NIiMe (8) in crystals. The tetrapeptide Boc-Val-Aib-Aib-Leu-NHMe (7) adopts an incipient 3(10)-helical conformation stabilized by three 4 -> 1 hydrogen bonds. The peptide Boc-Val-Aib-(D)Ala-Leu-NHMe (3) adopts a novel et-turn conformation, stabilized by three intramolecular hydrogen bonds (two 4 -> 1 and one 5 -> 1). The Aib-L(D)Ala segment adopts a type-I' beta-turn conformation. The observation of an NOE between Val (1) NH <-> HNCH(3) (5) in CD(3)OH suggests, that the solid state conformation is maintained in methanol solutions. (C) 2011 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 96: 744-756, 2011.

Investigating proline puckering states in diproline segments in proteins

In the current study, the puckering states of the Proline ring occurring in diproline segments (LPro-LPro) in proteins has been investigated with a segregation made on the basis of cis and trans states for the Pro-Pro peptide bond and the conformational states for the diproline segment to investigate the effects of conformation of the diproline segment on the corresponding puckering state of the Proline ring in the segment if any. The value of the endocyclic ring torsional angles of the pyrrolidine ring has been used for calculating and visualizing various puckering states using a proposed new sign convention (+/-) nomenclature. The results have been compared to that obtained in a previous study on peptides from this group. In this study, quite interestingly, the Planar (G) conformation that was present in 14.3% of the cases in peptides, appears to be nearly a rare conformation in the case of proteins (1.9%). The present study indicates that the (C-exo/C-exo), (C-exo/Twisted C-exo-C-endo) and (Twisted C-endo-C-exo/Twisted C-endo-C-exo) categories are the most preferred combinations. For Proline rings in proteins, the states C-exo, Twisted C-exo-C-endo and Twisted C-endo-C-exo are the most preferred states. Within diproline segments, the pyrrolidine ring conformations do not show a strong co-relation to the backbone conformation in which they are observed. It is likely that five-membered rings have a considerable plasticity of structure and are readily deformed to accommodate a variety of energetically preferred backbone conformations.

Steric and Electronic Interactions Controlling the cis/trans Isomer Equilibrium at X-Pro Tertiary Amide Motifs in Solution

A systematic understanding of the noncovalent interactions that influence the structures of the cis conformers and the equilibrium between the cis and the trans conformers, of the X-Pro tertiary amide motifs, is presented based on analyses of H-1-, C-13-NMR and FTIR absorption spectra of two sets of homologous peptides, X-Pro-Aib-OMe and X-Pro-NH-Me (where X is acetyl, propionyl, isobutyryl and pivaloyl), in solvents of varying polarities. First, this work shows that the cis conformers of any X-Pro tertiary amide motif, including Piv-Pro, are accessible in the new motifs X-Pro-Aib-OMe, in solution. These conformers are uniquely observable by FTIR spectroscopy at ambient temperatures and by NMR spectroscopy from temperatures as high as 273 K. This is made possible by the persistent presence of n(i-1i)* interactions at Aib, which also influence the disappearance of steric effects at these cis X-Pro rotamers. Second, contrary to conventional understanding, the energy contribution of steric effects to the cis/trans equilibrium at the X-Pro motifs is found to be nonvariant (0.54 +/- 0.02 kcal/mol) with increase in steric bulk on the X group. Third, the current studies provide direct evidence for the weak intramolecular interactions namely the n(i-1i)*, the N-Pro center dot center dot center dot Hi+1 (C(5)a), and the C-7 hydrogen bond that operate and influence the structures, stabilities, and dynamics between different conformational states of X-Pro tertiary amide motifs. NMR and IR spectral data suggest that the cis conformers of X-Pro motifs are ensembles of short-lived rotamers about the C-X-N-Pro bond. (c) 2013 Wiley Periodicals, Inc. Biopolymers 101: 66-77, 2014.

Energy Hyperspace for Stacking Interaction in AU/AU Dinucleotide Step: Dispersion-Corrected Density Functional Theory Study

Double helical structures of DNA and RNA are mostly determined by base pair stacking interactions, which give them the base sequence-directed features, such as small roll values for the purine-pyrimidine steps. Earlier attempts to characterize stacking interactions were mostly restricted to calculations on fiber diffraction geometries or optimized structure using ab initio calculations lacking variation in geometry to comment on rather unusual large roll values observed in AU/AU base pair step in crystal structures of RNA double helices. We have generated stacking energy hyperspace by modeling geometries with variations along the important degrees of freedom, roll, and slide, which were chosen via statistical analysis as maximally sequence dependent. Corresponding energy contours were constructed by several quantum chemical methods including dispersion corrections. This analysis established the most suitable methods for stacked base pair systems despite the limitation imparted by number of atom in a base pair step to employ very high level of theory. All the methods predict negative roll value and near-zero slide to be most favorable for the purine-pyrimidine steps, in agreement with Calladine's steric clash based rule. Successive base pairs in RNA are always linked by sugar-phosphate backbone with C3-endo sugars and this demands C1-C1 distance of about 5.4 angstrom along the chains. Consideration of an energy penalty term for deviation of C1-C1 distance from the mean value, to the recent DFT-D functionals, specifically B97X-D appears to predict reliable energy contour for AU/AU step. Such distance-based penalty improves energy contours for the other purine-pyrimidine sequences also. (c) 2013 Wiley Periodicals, Inc. Biopolymers 101: 107-120, 2014.

Stacking Interactions in RNA and DNA: Roll-Slide Energy Hyperspace for Ten Unique Dinucleotide Steps

Understanding dinucleotide sequence directed structures of nuleic acids and their variability from experimental observation remained ineffective due to unavailability of statistically meaningful data. We have attempted to understand this from energy scan along twist, roll, and slide degrees of freedom which are mostly dependent on dinucleotide sequence using ab initio density functional theory. We have carried out stacking energy analysis in these dinucleotide parameter phase space for all ten unique dinucleotide steps in DNA and RNA using DFT-D by B97X-D/6-31G(2d,2p), which appears to satisfactorily explain conformational preferences for AU/AU step in our recent study. We show that values of roll, slide, and twist of most of the dinucleotide sequences in crystal structures fall in the low energy region. The minimum energy regions with large twist values are associated with the roll and slide values of B-DNA, whereas, smaller twist values correspond to higher stability to RNA and A-DNA like conformations. Incorporation of solvent effect by CPCM method could explain the preference shown by some sequences to occur in B-DNA or A-DNA conformations. Conformational preference of BII sub-state in B-DNA is preferentially displayed mainly by pyrimidine-purine steps and partly by purine-purine steps. The purine-pyrimidine steps show largest effect of 5-methyl group of thymine in stacking energy and the introduction of solvent reduces this effect significantly. These predicted structures and variabilities can explain the effect of sequence on DNA and RNA functionality. (c) 2014 Wiley Periodicals, Inc. Biopolymers 103: 134-147, 2015.

Exploring the Consequences of a Representative ``Disallowed'' Conformation of Aib on a 3(10)-Helical Fold

The structural effects of a representative disallowed conformation of Aib on the 3(10)-helical fold of an octapeptidomimetic are explored. The 1D (H-1, C-13) & 2D NMR, FT-IR and CD data reveal that the octapeptide 1, adopts a 3(10)-helical conformation in solution, as it does in its crystal structure. The C-terminal methyl carboxylate (CO2Me) of 1 was modified into an 1,3-oxazine (Oxa) functional group in the peptidomimetic 2. This modification results in the stabilization of the backbone of the C-terminal Aib (Aib*-Oxa) of 2, in a conformation (phi, =180, 0) that is natively disallowed to Aib. Consequent to the presence of this natively disallowed conformation, the 3(10)-helical fold is not disrupted in the body of the peptidomimetic 2. But the structural distortions that do occur in 2 are primarily in residues in the immediate vicinity of the natively disallowed conformation, rather than in the whole peptide body. Non-native electronic effects resulting from modifications in backbone functional groups can be at the origin of stabilizing residues in natively disallowed conformations. (c) 2014 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 104: 21-36, 2015.

Exploring the Consequences of a Representative ``Disallowed'' Conformation of Aib on a 3(10)-Helical Fold

The structural effects of a representative ``disallowed'' conformation of Aib on the 3(10)-helical fold of an octapeptidomimetic are explored. The 1D (H-1, C-13) & 2D NMR, FT-IR and CD data reveal that the octapeptide 1, adopts a 3(10)- helical conformation in solution, as it does in its crystal structure. The C-terminal methyl carboxylate (CO2Me) of 1 was modified into an 1,3-oxazine (Oxa) functional group in the peptidomimetic 2. This modification results in the stabilization of the backbone of the C-terminal Aib (Aib(star)-Oxa) of 2, in a conformation (phi, psi = 180, 0) that is natively disallowed to Aib. Consequent to the presence of this natively disallowed conformation, the 3(10)- helical fold is not disrupted in the body of the peptidomimetic 2. But the structural distortions that do occur in 2 are primarily in residues in the immediate vicinity of the natively disallowed conformation, rather than in the whole peptide body. Non-native electronic effects resulting from modifications in backbone functional groups can be at the origin of stabilizing residues in natively disallowed conformations. (C) 2014 Wiley Periodicals, Inc. Biopolymers

Exploring the Consequences of a Representative ``Disallowed'' Conformation of Aib on a 3(10)-Helical Fold

The structural effects of a representative ``disallowed'' conformation of Aib on the 3(10)-helical fold of an octapeptidomimetic are explored. The 1D (H-1, C-13) & 2D NMR, FT-IR and CD data reveal that the octapeptide 1, adopts a 3(10)- helical conformation in solution, as it does in its crystal structure. The C-terminal methyl carboxylate (CO2Me) of 1 was modified into an 1,3-oxazine (Oxa) functional group in the peptidomimetic 2. This modification results in the stabilization of the backbone of the C-terminal Aib (Aib(star)-Oxa) of 2, in a conformation (phi, psi = 180, 0) that is natively disallowed to Aib. Consequent to the presence of this natively disallowed conformation, the 3(10)- helical fold is not disrupted in the body of the peptidomimetic 2. But the structural distortions that do occur in 2 are primarily in residues in the immediate vicinity of the natively disallowed conformation, rather than in the whole peptide body. Non-native electronic effects resulting from modifications in backbone functional groups can be at the origin of stabilizing residues in natively disallowed conformations. (C) 2014 Wiley Periodicals, Inc. Biopolymers

Effect of methylene group insertions on the structural rigidity of Aib containing helices

Nonprotein amino acids are being extensively used in the design of synthetic peptides to create new structure mimics. In this study we report the effect of methylene group insertions in a heptapeptide Boc-Ala(1)-Leu(2)-Aib(3)-Xxx(4)-Ala(5)-Leu(6)-Aib(7)-OMe which nicely folds into a mixed 3(10)-/-helical structure when Xxx= Ala. Analogs of this peptide have been made and studied by replacing central Xxx(4) residue with Glycine (-residue), -Alanine (-la), -aminobutyric acid (Gaba), and epsilon-aminocaproic acid (epsilon-Aca). NMR and circular dichroism were used to study the solution structure of these peptides. Crystals of the peptides containing alanine, -la, and Gaba reveal that increasing the number of central methylene (-CH2-) groups introduces local perturbations even as the helical structure is retained. (c) 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 104: 720-732, 2015.