5 research outputs found
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
Novel approach for estimating solubility of solid drugs in supercritical carbon dioxide and critical properties using direct and inverse artificial neural network (ANN)
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