Design and Synthesis of Peptides with Hybrid Helix-Turn-Helix (HTH) Motif and Their Conformational Study

• Published in: Journal of organic chemistry Vol. 79; no. 18; pp. 8614 - 8628
• Main Authors: Sharma, Gangavaram V. M, Thodupunuri, Prashanth, Sirisha, Katukuri, Basha, Shaik Jeelani, Gurava Reddy, Pottireddygari, Sarma, Akella V. S
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 19.09.2014; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Circular Dichroism; Helix-Turn-Helix Motifs; Hydrogen Bonding; Magnetic Resonance Spectroscopy; Molecular Conformation; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Peptides - chemical synthesis; Peptides - chemistry; Physical Sciences; Protein Structure, Tertiary; Science & Technology; Stereoisomerism; BETA-AMINO ACID; MOLECULAR-DYNAMICS; FOLDAMERS; LAC REPRESSOR; NMR STRUCTURE; ALTERNATING ALPHA-AMINO; SECONDARY STRUCTURE; PROTEINS; BACKBONE; MIXED HELICES
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo501267k

The present study is aimed at the design and synthesis of peptides with hybrid helix-turn-helix (HTH) motif and their conformational analysis (NMR, MD, and CD studies). The requisite peptides with heterogeneous backbones were prepared from β-, γ-, and δ-amino acids with carbohydrate side chains and α-amino acid, l-Ala. The α/β-peptides were prepared from (S)-β-Caa(l) (C-linked carbo-β-amino acid with D-lyxo furanoside side chain) and l-Ala with a 1:1 alternation. The α/β-peptides with “helix-turn” motif displayed a 11/9-helix nucleating a 13-atom H-bonding turn. The α/β-octapeptides showed the presence of HTH structures with bifurcated 11/15-H-bonded turn. Further, the α/β-hexapeptide with HT motif, independently on coupling with γ/α/γ/α- and δ/α/δ/α-tetrapeptides at the C-terminus provided access to the decapeptides with “hybrid HTH” motifs. The decapeptide (“α–β–α–β–α–β–γ–α–γ–α”) showed a hybrid HTH with “11/9/11/9/11/16/9/12/10” H-bonding, while the decapeptide (“α–β–α–β–α–β–δ−α–δ−α”) revealed the presence of a “11/9/11/9/11/17/9/13/11” helical pattern. The above peptides thus have shown compatibility between different types of helices and serendipitous bifurcated 11/16- and 11/17-turns. The present study thus provided the first opportunity for the design and study of “hybrid HTH” motifs with more than one kind of helical structures in them.