A Case Study of the Conformation of Poly(alpha-aminoisobutyric acid): alpha- or 310-Helix

The relative stabilities of a- and Blo-helical structures for polymers of a-aminoisobutyric acid (Aib) have been worked out, using the classical potential energy functions. To make a comparative study, we have used Buckingham "6-exp" and Kitaigorodsky's potential functions. Conformational analysis of the dipeptide segment with Aib residue indicates the necessity for nonplanar distortion of the peptide unit, which is a common feature in the observed crystal structures with Aib residues. In the range of Aw -10 to +loo studied, a-helical conformations are preferred in the region -3" < Aw < +loo, and Blo-helical conformations are preferred in the region -3" > Aw > -10'. Minimum energy conformations for right-handed structures are found in the +ue region of Aw and correspondingly for left-handed structures in the -ue region of Aw. For Aw - 6", a-helical structures have four- or near fourfold symmetry with h - 1.5 A. Such a helix with n = 4 and h = 1.5 A is termed an a'-helix. This structure is found to be consistent with the electron diffraction data of Malcolm3 and energetically more favorable than the standard 310-helix

The stereochemistry of a-aminoisobutyric acid containing peptides

a-Aminoisobutyric acid (Aib), * a nonprotein amino acid first described synthetically, I has been found in diverse sources, ranging from peptides of microbial origin2s3 to the Murchison mete~r i te.E~a rly studies of the chemistry of Aib were directed towards the synthesis of model peptides containing this "sterically hindered" amino There have been several reports on the synthesis of Aib containing analogs of biologically active peptides

Multiple Conformational States of a Pro-Pro Peptide. Solid-State and Solution Conformations of Boc-Aib-Pro-Pro-NHMe

The solid-state and solution conformations of the model peptide Boc-Aib-Pro-Pro-NHMe have been studied by X-ray diffraction and NMR. The peptide adopts a poly(pro1ine 11) conformation in the solid state. Two molecules are observed in the asymmetric unit differing in the geometry (cisltrans) of the urethane group. The molecules are held together in the crystal by a complex network of hydrogen bonds involving three molecules of water, which cocrystallize. Dissolution of single crystals at low temperature (\sim 233 K) permits NMR observation of the solid-state conformer. In solution, the peptide undergoes a trans-cis isomerization of the Pro-Pro bond. Low- temperature NMR measurements allow the detection of three conformational states of the Pro-Pro segment. Both cis’ and trans’ rotational isomers about the $C^\alpha -CO$ $(\psi)$ bond of Pro-3 are detectable at low temperatures. Theoretical calculations suggest an appreciable activation barrier to $\psi$ rotation. Temperature and solvent dependence of NH chemical shifts provide evidence for an intramolecular hydrogen bond, involving the NHMe group in the cis Pro-Pro conformer. Energy calculations suggest the possibility of a type VI $\beta$-turn conformation stabilized by a 4 $\rightarrow$ 1 hydrogen bond between the Aib-1 CO and NHMe groups

Type II \beta-Turn Conformation of Pivaloyl-L-Prolyl-\alpha-Aminoisobutyryl-N-Methylamide: Theoretical, Spectroscopic, and X-Ray Studies

Pivaloyl-L-Pro-Aib-N-methylamide has been shown to possess one intramolecular hydrogen bond in ${({CD}_3)}_2SO$ solution, by 'H-nmr methods, suggesting the existence of \beta-turns, with Pro-Aib as the corner residues. Theoretical conformational analysis suggests that Type II \beta-turn conformations are about 2 kcal $mol^{-1}$ more stable than Type III structures. A crystallographic study has established the Type II \beta-turn in the solid state. The molecule crystallizes in the space group ${P2}_1$ with a = 5.865 A, b = 11.421 A, c = 12.966 A, \beta = 97.55 deg, and Z = 2. The structure has been refined to a final R value of 0.061. The Type II \beta-turn conformation is stabilized by an intramolecular 4 \rightarrow 1 hydrogen bond between the methylamide NH and the pivaloyl CO group. The conformational angles are ${\phi}_{pro}$ = -57.8 deg, ${\psi}_{pro}$ = 139.3 deg, ${\phi}_{Aib}$ = 61.4 deg, and ${\psi}_{Aib}$ = 25.1 deg. The Type II \beta-turn conformation for Pro-Aib in this peptide is compared with the Type III structures observed for the same segment in larger peptides

Type II beta-turn conformation of pivaloyl-L-prolyl-alpha-aminoisobutyryl-N-methylamide: Theoretical, spectroscopic, and X-ray studies

Pivaloyl-L-Pro-Aib-N-methylamide has been shown to possess one intramolecular hydrogen bond in (CD3)2SO solution, by 1H-nmr methods, suggesting the existence of beta -turns, with Pro-Aib as the corner residues. Theoretical conformational analysis suggests that Type II beta-turn conformations are about 2 kcal mol-1 more stable than Type III structures. A crystallographic study has established the Type II beta-turn in the solid state. The molecule crystallizes in the space group P21 with a = 5.865 Å, b = 11.421 Å, c = 12.966 Å, beta = 97.55°, and Z = 2. The structure has been refined to a final R value of 0.061. The Type II -turn conformation is stabilized by an intramolecular 4 1 hydrogen bond between the methylamide NH and the pivaloyl CO group. The conformational angles are Pro = -57.8°, Pro = 139.3°, Aib = 61.4°, and Aib = 25.1°. The Type II beta-turn conformation for Pro-Aib in this peptide is compared with the Type III structures observed for the same segment in larger peptides

Molecular structure of a cyclic tetrapeptide disulfide. A novel 310 helical conformation with an S-S bridge

The crystal structure of the cyclic peptide disulfide Boc-Cys-Pro-Aib-Cys-NHMe has been determined by X-ray diffraction. The peptide crystallizes in the space group P212121, with A = 8.646(1), B = 18.462(2), C = 19.678(3)Å and Z = 4. The molecules adopt a highly folded compact conformation, stabilized by two intramolecular 4→ 1 hydrogen bonds between the Cys (1) and Pro (2) CO groups and the Cys (4) and methylamide NH groups, respectively. The backbone conformational angles for the peptide lie very close to those expected for a 310 helix. The S-S bridge adopts a right handed twist with a dihedral angle of 82°. The structure illustrates the role of stereochemically constrained residues, in generating novel peptide conformations. Aib, α-aminoisobutyric acid; Z, benzyloxycarbonyl; Boc, t-butyloxycarbonyl; OMe, methyl ester; OBz, benzyl ester; NHMe, N-methylamide; Tosyl, p-toluenesulfonyl

Type II beta-turn conformation of pivaloyl-L-prolyl-a-aminoiso-butyryl-N-methylamide: Theoretical, spectroscopic and X-ray studies

Pivaloyl-L-Pro-Aib-N-methylamihdaes been shown to possess one intramolecular hydrogen bond in (CD&SO solution, by 'H-nmr methods, suggesting the existence of p-turns, with Pro-Aib as the corner residues. Theoretical conformational analysis suggests that Type II P-turn conformations are about 2 kcal mol-' more stable than Type 111 structures. A crystallographic study has established the Type I1 /%turn in the solid state. The molecule crystallizes in the space group P21 with a = 5.865 8, b = 11.421 A, c = 12.966 A, /3 = 97.55", and 2 = 2. The structure has been refined to a final R value of 0.061. The Type I1 p-turn conformation is stabilized by an intramolecular 4 - 1 hydrogen bond between the methylamide NH and the pivaloyl CO group. The conformational angles are @pro= -57.8", $pro = 139.3', @Aib = 61.4', and$Ajb = 25.1'. The Type 11 /%turn conformation for Pro-Aib in this peptide is compared with the Type I11 structures observed for the same segment in larger peptides

The Crystal Structure of Benzyloxycarbonyl-(α−aminoisobutyryl)2{(\alpha-aminoisobutyryl)}_2-L-Alanyl Methyl Ester

Crystals of the title compound, $C_{20}H_{29}N_3O_6$, are monoclinic, space group ${P2}_1$, with a = 8.839 (3), b = 10.818 (3), c = 11.414 (2) A, \beta = 95.69 (2) deg, Z = 2; final R = 0.053. The molecular conformation is defined by the following angles (\phi, \psi): Aib-1 58.1, 36.8; Aib-2 68.3, 18.6; Ala-3 (\phi) = 136.2 deg. The molecule adopts a type III' \beta-turn conformation stabilized by an intramolecular hydrogen bond between the CO of the benzyloxycarbonyl group and the NH of the alanyl residue. The hydrogen-bond parameters are N . . . O 2.904 A and \angle NH . . . O 156.9 deg