Alpha-gamma hybrid peptides that contain the conformationally constrained gabapentin residue: characterization of mimetics of chain reversals.
The crystal structures of four dipeptides that contain the stereochemically constrained gamma-amino acid residue gabapentin (1-(aminomethyl)cyclohexaneacetic acid Gpn) are described. The molecular conformation of Piv-Pro-Gpn-OH (1), reveals a beta-turn mimetic conformation, stabilized by a ten atom C[bond]H...O hydrogen bond between the Piv CO group and the pro S hydrogen of the Gpn CH(2)[bond]CO group. The peptides Boc-Gly-Gpn-OH (2), Boc-Aib-Gpn-OH (3), and Boc-Aib-Gpn-OMe (4) form compact, folded structures, in which a distinct reversal of polypeptide chain direction is observed. In all cases, the Gpn residue adopts a gauche,gauche (g,g) conformation about the C(gamma)[bond]C(beta) (theta(1)) and C(beta)[bond]C(alpha) (theta(2)) bonds. Two distinct Gpn conformational families are observed. In peptides 1 and 3, the average backbone torsion angle values for the Gpn residue are phi=98 degrees, theta(1)=-62 degrees, theta(2)=-73 degrees, and psi=79 degrees, while in peptide 2 and 4 the average values are phi=-103 degrees, theta(1)=-46 degrees, theta(2)=-49 degrees, and psi=-92 degrees. In the case of 1 and 3, an intramolecular nine-membered O[bond]H...O hydrogen bond is formed between the C[double bond]O of the preceding residue and the terminal carboxylic acid OH group. All four alpha-gamma dipeptide sequences yield compact folded backbone conformations; this suggests that the Gpn residue may be employed successfully in the design of novel folded structures.
Aravinda
Subrayashastry
S
Department of Physics, Indian Institute of Science, Bangalore, 560 012, India.
Ananda
Kuppanna
K
Shamala
Narayanaswamy
N
Balaram
Padmanabhan
P
D000085:Acetates / Q000737:chemistry*; D000588:Amines; D040761:Biomimetic Materials / Q000737:chemistry; D018360:Crystallography, X-Ray; D003509:Cyclohexanecarboxylic Acids; D004151:Dipeptides / Q000737:chemistry*; D000077206:Gabapentin; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D017433:Protein Structure, Secondary; D013237:Stereoisomerism; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D004151:Dipeptides; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin