Conformation of a 16-residue zervamicin IIA analog peptide containing three different structural features: 3(10)-helix, alpha-helix, and beta-bend ribbon.

Abstract

Boc-Trp-Ile-Ala-Aib-Ile-Val-Aib-Leu-AibPro-Ala-Aib-Pro-Aib-Pro-Phe-OMe (where Boc is t-butoxycarbonyl and Aib is a-aminoisobutyric acid), a synthetic apolar analog of the membrane-active fungal peptide antibiotic zervamycin IIA, crystallizes in space group P1 with Z = 1 and cell parameters a = 9.086 ± 0. angles Hi range from -51°to -91°(average value -64°), and the torsion angles Pif range from -1°to -46°(average value -31°). There are 10 intramolecular NH-..OC hydrogen bonds in the helix and two direct head-to-tail hydrogen bonds between successive molecules. Two H20 and two CH3OH solvent molecules fill additional space with appropriate hydrogen bonding in the head-to-tail region, and two additional 1120 molecules form hydrogen bonds with carbonyl oxygens near the curve in the helix at Pro-10. Since there is only one peptide molecule per cell in space group P1, the molecules repeat only by translation, and consequently the helices pack parallel to each other.Transmembrane pore formation by alamethicin and related membrane-modifying peptides containing a-aminoisobutyric acid (Aib) most likely involves lipid phase aggregation of helical peptide molecules, since individual 310-helices or a-helices have an inner pore much too small for the passage of ions (1). The role of specific side chains in promoting helix aggregation and the mode of aggregation are being studied by means of crystal-structure analyses of membrane-active peptides. The study began with a synthetic apolar analog of zervamicin IIA (2) in which Gln, Thr, and Hyp (Hyp is 4-hydroxyproline) have been replaced with Ala, Val, and Pro, respectively; the N-terminus has been blocked with tbutoxycarbonyl (Boc) rather than acetyl; and the C-terminal alcohol function has been replaced by a methyl ester. The 5 structure of the hexadecapeptide Boc-Trp-Ile-Ala-Aib-Ile-10 15

Cα‐Methyl proline: A unique example of split personality

“…Indeed, the -(Aib-L-Pro) n -sequence was shown to fold into a variant of the right-handed 3 10 -helix, known as the b-bend ribbon. 15,16 This helix is stabilized by 50% of the intramolecular H-bonds occurring in a regular 3 10 -helix. An additional property of Pro is that it occurs extensively in the collagen triple helix.…”

Folding, aggregation and molecular recognition in peptides

“…Linear peptides form fl-sheets (Karle, Karle, Mastropaolo, Camerman & Camerman, 1983), 3,0-helices for short peptides (Toniolo et al, 1983), ahelices for longer peptides Fox & Richards, 1982), double helices (Benedetti, di Blasio, Pedone, Lorenzi, Tomasic & Gramlich, 1979;Langs, 1988) and mixed helices consisting of a 3,0/ahelix and a fl-ribbon twisted into a helix (Karle, Flippen-Anderson, Sukumar & Balaram, 1987;Karle, Flippen-Anderson, Agarwalla & Balaram, 1991). The latter has been established in Leu-zervamicin and a 16-residue apolar analog that contain in their sequences three Pro or Hyp (hydroxyproline) residues at positions 10, 13 and 15.…”

Crystal structure of [Leu1]zervamicin, a membrane ion-channel peptide: implications for gating mechanisms.

“…The unusual conformation and the probable mobility of the Gln"1 side chain strongly suggest the location of the gating mechanism during ion transport (see below). Additionally, the polar face is enhanced by the exposed backbone carbonyl oxygens in residues 6, 7, and 10, which do not participate in intrahelical hydrogen bonds ( N (5) N (6) OY (6) N (7) N (8) N (9) 06 (10) (10) 0 (8) 0 (9) 0E (13) (12) is almost identical to that of the backbone in the natural [Leul]zervamicin. The configuration of the Iva residue at position 4 is R, confirming an earlier stereochemical assignment (8).…”

“…The search model was based on the backbone atoms ofthe known structure ofa 16-residue apolar analog of zervamicin (12) and was followed by a partialstructure procedure (13) by which the atoms in the side chains were located. The detailed structure only of crystal A will be reported here.…”