Constrained phenylalanyl peptides via a [2+2+2]-cycloaddition strategy

Peptide modification potentially valuable for peptidomimetic and combinatorial chemistry applications is described involving a [2+2+2]-cycloaddition reaction leading to conformationally constrained phenylalanyl peptides

Mechanism-based protein design: Attempted "nucleation-condensation" approach to a possible minimal helix-bundle protein

In an intended mechanism-based de novo approach, a 22-mer peptide was so designed as to make it both a stereochemically nucleatable and hydrophobically condensable minimal globular protein. Framework-like nucleation of a triple-helix bundle was targeted by employing as folding nucleators composite beta-turns that could both nucleate helices and place them in close juxtaposition for possible interhelical interaction. To promote the targeted triple-helix bundle to condense as a globular protein, an amphipathic sequence pattern was adopted for possible hydrophobic interhelical interaction. A predominantly helicogenic 22-mer amphipathic peptide was thus designed, punctuating it with composite type II'-III and type II-Asx type beta-turns as the helix nucleators cum chain reversal elements. The peptide made by solid-phase synthesis was shown by NMR and CD to be a nascent and distorted triple-helix bundle in a trifluoroethanol (TFE)-water mixture, but more or less a random coil in water. A fold nucleation effect is evident in the TFE-water mixture, but apparently the hydrophobic effect cannot sustain the peptide conformational order in water. A lack of synergy between folding nucleation and hydrophobic condensation of the peptide is possible. Indeed, a mismatch between the sequential H, P pattern of the peptide and its nascent-type globular fold in a TFE-water mixture is evident based on a simulated annealing study guided by NMR. (C) 2003

Conformational effects of C-alpha,C-alpha-dipropargylglycine as a constrained residue

A useful synthon to approach artificial phenylalanyl peptides in a [2 + 2 + 2] cycloaddition reaction, C-alpha,C-alpha-dipropargylglycine (Dprg) is examined for its conformational preferences as a constrained residue. Crystal structure analysis and preliminary NMR results establish possible preference of the residue for folded (alpha) rather than extended (beta) region of the phi,psi conformational space. Boc-Dprg-L-Leu-OMe (1) displays two molecular conformations within the same crystallographic asymmetric unit, with Dprg in the alpha (R) or alpha (L) conformation, participating in a type I beta -turn or an alpha (L)-alpha (R)-type fold, in which Leu(2) assumes the alpha (R) conformation stereochemically favored for an L-chiral residue. Boc-Dprg-D-Val-L-Leu-OMe (2) displays a type I ' beta -turn conformation in crystal, with both Dprg(1) and D-Val(2) assuming the alpha (L) conformation stereochemically favored for a D-chiral residue, with 4 --> 1 type hydrogen bond linking L-Leu(3) NH is with Boc CO. NMR analysis using temperature variation, solvent titration, and a spin probe study suggests a fully soh,ent-exposed nature of Dprg NH, ruling out a fully extended C-5-type conformation for this residue, and soli,ent sequestered nature of L-Leu(3) NH, suggesting possibility of a beta -turn due to Dprg assuming a folded conformation. (C) 2001 , Inc

Creating novel protein scripts beyond natural alphabets

Natural proteins are concatenated amino acids with definite handedness or chirality, with their spatial orientation being preferentially left handed or L-chiral. This paper discusses the biophysics of stereo-chemical perturbation to proteins using D-(α) amino acid and its utility as an additional design alphabet while scripting novel protein structures