title: Efficient access to enantiopure γ4-amino acids with proteinogenic side-chains and structural investigation of γ4-Asn and γ4-Ser in hybrid peptide helices.
abstract: Hybrid peptides composed of α- and β-amino acids have recently emerged as new class of peptide foldamers. Comparatively, γ- and hybrid γ-peptides composed of γ(4) -amino acids are less studied than their β-counterparts. However, recent investigations reveal that γ(4)-amino acids have a higher propensity to fold into ordered helical structures. As amino acid side-chain functional groups play a crucial role in the biological context, the objective of this study was to investigate efficient synthesis of γ(4)-residues with functional proteinogenic side-chains and their structural analysis in hybrid-peptide sequences. Here, the efficient and enantiopure synthesis of various N- and C-terminal free-γ(4)-residues, starting from the benzyl esters (COOBzl) of N-Cbz-protected (E)-α,β-unsaturated γ-amino acids through multiple hydrogenolysis and double-bond reduction in a single-pot catalytic hydrogenation is reported. The crystal conformations of eight unprotected γ(4)-amino acids (γ(4)-Val, γ(4)-Leu, γ(4)-Ile, γ(4)-Thr(OtBu), γ(4)-Tyr, γ(4)-Asp(OtBu), γ(4)-Glu(OtBu), and γ-Aib) reveals that these amino acids adopted a helix favoring gauche conformations along the central C(γ) -C(β) bond. To study the behavior of γ(4)-residues with functional side chains in peptide sequences, two short hybrid γ-peptides P1 (Ac-Aib-γ(4)-Asn-Aib-γ(4)-Leu-Aib-γ(4)-Leu-CONH2 ) and P2 (Ac-Aib-γ(4)-Ser-Aib-γ(4)-Val-Aib-γ(4)-Val-CONH2 ) were designed, synthesized on solid phase, and their 12-helical conformation in single crystals were studied. Remarkably, the γ(4) -Asn residue in P1 facilitates the tetrameric helical aggregations through interhelical H bonding between the side-chain amide groups. Furthermore, the hydroxyl side-chain of γ(4)-Ser in P2 is involved in the interhelical H bonding with the backbone amide group. In addition, the analysis of 87 γ(4)-residues in peptide single-crystals reveal that the γ(4)-residues in 12-helices are more ordered as compared with the 10/12- and 12/14-helices.
authors.affiliation: Department of Chemistry, Indian Institute of Science Education and Research (IISER), Dr. Homi Bhabha, Road, Pune-411008 (India), Fax: (+91) 20-2590-8186.
authors.forename: Sandip V
authors.initials: SV
authors.lastname: Jadhav
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Misra
authors.forename: Sumeet K
authors.initials: SK
authors.lastname: Singh
authors.forename: Hosahudya N
authors.initials: HN
authors.lastname: Gopi
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry; D001216:Asparagine / Q000737:chemistry*; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D017433:Protein Structure, Secondary; D012694:Serine / Q000737:chemistry*; D060327:Solid-Phase Synthesis Techniques
chemical_list: D000596:Amino Acids; D010455:Peptides; D012694:Serine; D001216:Asparagine
keywords: amino acids; crystal conformations; helical aggregation; hydrogenation; peptides