Showing papers by "Padmanabhan Balaram published in 1986"

Stereochemically constrained peptides. Theoretical and experimental studies on the conformations of peptides containing 1-aminocyclohexanecarboxylic acid

Abstract: Conformational energy calculations on the model system N-acetyl- 1 -aminocyclohexanecarboxylic acid N'methylamide (Ac-Acc6-NHMe), using an average geometry derived from 13 crystallographic observations, establish that the Acc6 residue is constrained to adopt conformations in the helical regions of In contrast, the a,a-dialkylated residue with linear hydrocarbon side chains, a,a-di-n-propylglycine favors fully extended backbone structures (6 1= $ = 180'). The crystal structures of two model peptides, Boc-(Acc6),-OMe (type 111 @-turn at -Acc6(1)-Acc6(2)-) and Boc-Pro-Acc6-Ala-OMe (type I1 P-turn at -Pro-Acc6-), establish that Acc6 residues can occupy either position of type 111 P-turns and the i + 2 position of type I1 @-turns. The stereochemical rigidity of these peptides is demonstrated in solution by NMR studies, which establish the presence of one intramolecular hydrogen bond in each peptide in CDCI, and (CDJ2S0. Nuclear Overhauser effects permit characterization of the @-turn conformations in solution and establish their similarity to the solid-state structures. The implications for the use of Acc6 residues in conformational design are considered.

Stereochemistry of α-aminoisobutyric acid peptides in solution: Conformations of decapeptides with a central triplet of contiguous L-amino acids

Abstract: The decapeptides $Boc-Aib-L-Val-Aib-Aib-{(L-Val)}_3-Aib-L-Val-Aib-OMe$ and $Boc-Aib-L-Leu- Aib-Aib-{(L-Leu)}_3-Aib-L-Leu-Aib-OMe$ have been studied in $CD{Cl}_3$ and ${({CD}_3)}_2SO$ solutions by 270-MHz' H-nmr. In $CD{Cl}_3$ the presence of eight intramolecularly hydrogen-bonded NH groups has been established, consistent with a $3_{10}$-helical conformation, for both decapeptides. In ${({CD}_3)}_2SO$ only seven solvent-shielded NH groups are observed, supporting either an \alpha-helical conformation or a partially unfolded $3_{10}$-helix. Ir studies provided supporting evidence for intramolecularly hydrogen-bonded structures in $CH{Cl}_3$, while CD studies suggest helical conformation in both decapeptides in various solvents. CD studies also support helical folding in the C-terminal hexapeptides. The central triplet of L-amino acids appears to destabilize $3_{10}$-helical conformations in polar solvents like ${({CD}_3)}_2SO$.

Parallel packing of alpha-helices in crystals of the zervamicin IIA analog Boc-Trp-Ile-Ala-Aib-Ile-Val-Aib-Leu-Aib-Pro-OMe.2H2O

Abstract: An apolar synthetic analog of the first 10 residues at the NH2-terminal end of zervamicin IIA crystallizes in the triclinic space group P1 with cell dimensions a = 10.206 +/- 0.002 A, b = 12.244 +/- 0.002 A, c = 15.049 +/- 0.002 A, alpha = 93.94 +/- 0.01 degrees, beta = 95.10 +/- 0.01 degrees, gamma = 104.56 +/- 0.01 degrees, Z = 1, C60H97N11O13 X 2H2O. Despite the relatively few alpha-aminoisobutyric acid residues, the peptide maintains a helical form. The first intrahelical hydrogen bond is of the 3(10) type between N(3) and O(0), followed by five alpha-helix-type hydrogen bonds. Solution 1H NMR studies in chloroform also favor a helical conformation, with seven solvent-shielded NH groups. Continuous columns are formed by head-to-tail hydrogen bonds between the helical molecules along the helix axis. The absence of polar side chains precludes any lateral hydrogen bonds. Since the peptide crystallizes with one molecule in a triclinic space group, aggregation of the helical columns must necessarily be parallel rather than antiparallel. The packing of the columns is rather inefficient, as indicated by very few good van der Waals' contacts and the occurrence of voids between the molecules.

Stereochemistry of Peptides Containing 1-Aminocyclopentanecarboxylic Acid $({Acc}^5)$ : Solution and Solid-state Conformations of $Boc-{Acc}^5-{Acc}^5-NHMe$

Abstract: The conformational analysis of a protected homodipeptide of 1-aminocyclopentanecarboxylic acid $({Acc}^5)$ has been carried out. 'H-nmr studies establish a \beta-turn conformation for $Boc-{Acc}^5-{Acc}^5-NHMe$ 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 \beta-turn conformation in the solid state stabilized by a 4 \rightarrow 1 hydrogen bond between the Boc CO and methylamide NH groups. The \phi, \psi values for both ${Acc}^5$ residues are close to those expected for an ideal $3_{10}$-helical conformation (\phi = \pm 60 deg, \psi = \pm 30 deg).

Membrane channel forming polypeptides. Molecular conformation and mitochondrial uncoupling activity of antiamoebin, an alpha-aminoisobutyric acid containing peptide.

Abstract: The conformations of the 16-residue fungal peptide antiamoebin I were studied in DMSO soln. by 1- and 2-dimensional NMR techniques. A substantial no. of resonances in the 270-MHz 1H NMR spectrum were assigned. Intramolecularly H-bonded (solvent inaccessible) NH groups were identified by detg. solvent and temp.dependence of NH chem.shifts and rates of H-D exchange.Ten backbone NH groups are inaccessible to solvent, whereas 3 NH groups assigned to phenylalanine-1, aminoisobutyrate-2, and -8 residues are exposed to solvent.The NMR results,together with the stereochem.constraints imposed by the presence of a-aminoisobutyryl, isovalyl, prolyl, and 4-hydroxypropyl residues, favor a highly ordered structure. Two backbone conformations consistent with the data are considered. Antiamoebin is shown to be an effective uncoupler of oxidative phosphorylation in rat liver mitochondria, providing evidence for its membrane-modifying activity.

A rapid procedure for the resolution of racemic gossypol

Abstract: Racemic gossypol [(±)-I] was resolved rapidly and efficiently by high-performance liq. chromatog. sepn. of the diastereoisomeric adducts of (±)-I with L-phenylalaninol on an achiral, reversed-phase, C18 column. The sepd. adducts were hydrolyzed by 2M HCl to give (+)- and (-)-I with 50-60% recovery.

Conformations of the amino terminal tetrapeptide of emerimicins and antiamoebin in solution and in the solid state

Abstract: The conformations of Boc-l-Phe-(AiB)3-OH (1) and Boc-l-Phe-(Aib)3-OMe (2) which correspond to the amino terminal sequence of the emerimicins and antiamoebins have been studied in solution using 270 MHz 1H n.m.r. In dimethyl sulphoxide solution both peptides show the presence of two strongly solvent shielded Aib NH groups, consistent with a consecutive β-turn conformation, involving the Aib(3) and Aib(4) NH groups in intramolecular 4 → I hydrogen bonds. This folded conformation is maintained for 2 in chloroform solution. Nuclear Overhauser effect studies provide evidence for a Type II Phe-Aib β-turn. An X-ray diffraction study of Boc-(d,l)-Phe-(Aib)3-OH establishes a single type III(III′) β-turn conformation with Aib(2)-Aib(3) as the corner residues. A single intramolecular 4 → I hydrogen bond between Phe(I) CO and Aib(4) NH groups is observed in the crystal. The solution conformation may incorporate a consecutive type II-III′ structure for the Phe(1)-Aib(2)-Aib(3) segment, with the initial type II β-turn being destabilized by intermolecular interactions in the solid state.