DESIGN AND SYNTHESIS OF NOVEL NONPOLAR HOST PEPTIDES FOR THE DETERMINATION OF THE 3(10)-HELIX AND ALPHA-HELIX COMPATIBILITIES OF ALPHA-AMINO-ACID BUILDING-BLOCKS - AN ASSESSMENT OF ALPHA,ALPHA-DISUBSTITUTED GLYCINES

The present work describes three novel nonpolar host peptide sequences that provide a ready assessment of the 3(10)- and alpha-helix compati bilities of natural and unnatural amino acids at different positions o f small- to medium-size peptides. The unpolar peptides containing Ala, Aib, and a C-terminal p-iodoanilide group were designed in such a way that the peptides could be rapidly assembled in a modular fashion, we re highly soluble in solvent mixtures of triflouroethanol and H2O for CD-and two-dimensional (2D) nmr spectroscopic analyses, and showed exc ellent crystallinity suited for x-ray structure analysis. To validate our approach we synthesized 9-mer peptides 79a-96 (Table IV), 12-mer p eptides 99-110c (Table V), and 10-mer peptides 120a-125d and 129-133 ( Table VI and Scheme 8) incorporating a series of optically pure cyclic and open-chain (R)- and (S)-alpha, alpha-disubstituted glycines I-IO (Figure 2). These amino acids are known to significantly modulate the conformations of small peptides. Based on x-ray structures of 9-mers 7 9a, 80, and 87 (Figures 4-7), 10-mers 124c, 131, and 132 (Figures 9-12 ), and 12-mer peptide 102b (Figure 13), CD spectra of all peptides rec orded in acidic, neutral, and basic media and detailed 2D-nmr analyses of 9-mer peptide 86 and 12-mer 102b, several interesting conformation al observations were made. Especially interesting results were obtaine d using the convex constraint CD analysis proposed by Fasman on 9-mer peptides 79a-d, 80, 81, 86, and 87, which allowed us to determine the relative content of 3(10)- and alpha-helical conformations. These resu lts were fully supported by the corresponding x-ray and 2D-nmr analyse s. As a striking example we Sound that the (S)- and (R)-beta-tetralin derived amino acids (R)- and (S)-1 show excellent alpha-helix stabilis ation, more pronounced than Aib and Ala. These novel reference peptide sequences should help establish a scale for natural and unnatural ami no acids concerning their intrinsic 3(10)- and alpha-helix compatibili ties at different positions of medium-sized peptides and thus improve our understanding in the folding processes of peptides. (C) 1997 John Wiley & Sons, Inc.