Crystallographic characterization of the alpha,gamma C-12 helix in hybrid peptide sequences

The solid-state conformations of two alpha gamma hybrid peptides Boc-Aib-gamma(4)(R)Ile](4)-OMe 1 and Boc-Aib-gamma(4)(R)Ile](5)-OMe 2 are described. Peptides 1 and 2 adopt C-12-helical conformations in crystals. The structure of octapeptide 1 is stabilized by six intramolecular 4 -> 1 hydrogen bonds, forming 12 atom C-12 motifs. The structure of peptide 2 reveals the formation of eight successive C-12 hydrogen-bonded turns. Average backbone dihedral angles for alpha gamma C-12 helices are peptide 1, Aib; phi (degrees) = -57.2 +/- 0.8, psi (degrees) = -44.5 +/- 4.7; gamma(4)(R)Ile; phi (degrees) = -127.3 +/- 7.3, theta(1) (degrees) = 58.5 +/- 12.1, theta(2) (degrees)= 67.6 +/- 10.1, psi (degrees) = -126.2 +/- 16.1; peptide 2, Aib; phi (degrees) = -58.8 +/- 5.1, psi (degrees) = -40.3 +/- 5.5; psi(4)(R)Ile; phi (degrees) = -123.9 +/- 2.7, theta(1) (degrees) = 53.3 theta 4.9, theta(2) (degrees) = 61.2 +/- 1.6, psi (degrees) = -121.8 +/- 5.1. The tendency of gamma(4)-substituted residues to adopt gauche-gauche conformations about the C-alpha-C-beta and C-beta-C-gamma bonds facilitates helical folding. The alpha gamma C-12 helix is a backbone expanded analog of alpha peptide 3(10) helix. The hydrogen bond parameters for alpha peptide 3(10) and alpha-helices are compared with those for alpha gamma hybrid C-12 helix. Copyright (C) 2016 European Peptide Society and John Wiley & Sons

Temperature-Induced Reversible First-Order Single Crystal to Single Crystal Phase Transition in Boc-gamma(4)(R)Val-Val-OH: Interplay of Enthalpy and Entropy

Crystals of Boc-gamma y(4)(R)Val-Val-OH undergo a reversible first-order single crystal to single crystal phase transition at T-c approximate to 205 K from the orthorhombic space group P22(1)2(1) (Z' = 1) to the monoclinic space group P2(1) (Z' = 2) with a hysteresis of similar to 2.1 K. The low-temperature monoclinic form is best described as a nonmerohedral twin with similar to 50% contributions from its two components. The thermal behavior of the dipeptide crystals was characterized by differential scanning calorimetry experiments. Visual changes in birefringence of the sample during heating and cooling cycles on a hot-stage microscope with polarized light supported the phase transition. Variable-temperature unit cell check measurements from 300 to 100 K showed discontinuity in the volume and cell parameters near the transition temperature, supporting the first-order behavior. A detailed comparison of the room-temperature orthorhombic form with the low-temperature (100 K) monoclinic form revealed that the strong hydrogen-bonding motif is retained in both crystal systems, whereas the non-covalent interactions involving side chains of the dipeptide differ significantly, leading to a small change in molecular conformation in the monoclinic form as well as a small reorientation of the molecules along the ac plane. A rigid-body thermal motion analysis (translation, libration, screw; correlation of translation and libration) was performed to study the crystal entropy. The reversible nature of the phase transition is probably the result of an interplay between enthalpy and entropy: the low-temperature monoclinic form is enthalpically favored, whereas the room-temperature orthorhombic form is entropically favored

Directing peptide conformation with centrally positioned pre-organized dipeptide segments: studies of a 12-residue helix and beta-hairpin

Secondary structure formation in oligopeptides can be induced by short nucleating segments with a high propensity to form hydrogen bonded turn conformations. Type I/III turns facilitate helical folding while type II'/I' turns favour hairpin formation. This principle is experimentally verified by studies of two designed dodecapeptides, Boc-Val-Phe-Leu-Phe-Val-Aib-Aib-Val-Phe-Leu-Phe-Val-OMe 1 and Boc-Val-Phe-Leu-Phe-Val- (D) Pro- (L) Pro-Val-Phe-Leu-Phe-Val-OMe 2. The N- and C-terminal flanking pentapeptide sequences in both cases are identical. Peptide 1 adopts a largely alpha-helical conformation in crystals, with a small 3(10) helical segment at the N-terminus. The overall helical fold is maintained in methanol solution as evidenced by NMR studies. Peptide 2 adopts an antiparallel beta-hairpin conformation stabilized by 6 interstrand hydrogen bonds. Key nuclear Overhauser effects (NOEs) provide evidence for the antiparallel beta-hairpin structure. Aromatic proton chemical shifts provide a clear distinction between the conformation of peptides 1 (helical) and 2 (beta-hairpin). The proximity of facing aromatic residues positioned at non-hydrogen bonding positions in the hairpin results in extensively ring current shifted proton resonances in peptide 2

Unconstrained Homooligomeric gamma-Peptides Show High Propensity for C-14 Helix Formation

Monosubstituted gamma(4)-residues (gamma(4)Leu, gamma(4)Ile, and gamma(4)Val) form helices even in short homooligomeric sequences. C-14 helix formation is established by X-ray diffraction in homooligomeric (gamma)(n) tetra-, hexa- and decapeptide sequences demonstrating the high propensity of gamma residues, with proteinogenic side chains, to adopt locally folded conformations