The results of an analysis on the presence of π-turns, characterized by an i ← i + 5 C=O···H-N intramolecular hydrogen bond, in the X-ray diffraction structures of peptides are discussed. The survey returned a total of 55 π-turn occurrences in linear and cyclic peptides. π-Turns characterized by a helical conformation for residue i + 4, but with a screw sense opposite to that of the three preceding residues, are largely prevailing. They are often found at the C-end of incipient or fully developed α-helices, 310-helices, and mixed α-/310-helices, thus acting as a C-capping motif. However, the structures of two linear peptides and 15 cyclopeptides indicate that these types of π-turns can exist in isolation, without the support of a preceding helix. The frequent presence of additional intramolecular hydrogen bonds internal to the π-turn is also investigated. Cyclopeptides offered examples of two types of π-turns that have no parallel in the structures of proteins. Differently from proteins, π-turns characterized by helical ϕ, ψ sets of the same screw sense for all internal residues are hitherto unreported in the X-ray diffraction structures of peptides. A suggestion for the rational design in peptides/peptidomimetics of a π-turn featuring the screw-sense reversal of residue i + 4 is proposed.

In this work, we developed two new polyfunctional hybrid systems in which the presence of Fc redox “antennas” on peptide scaffolds allows for a modulation of their electronic properties. Specifically, we synthesized two helical hexapeptides containing four Aib (α-amionoisobutyric acid) and two L-Dap (2,3-diamino propionic acid) residues. L-Dap side chains were then functionalized with Fc moieties. The structures of the two 310 helical peptides, namely Z-Aib-L-Dap(Fc)-Aib-Aib-L-Dap(Fc)-Aib-NH-iPr and Z-Aib-L-Dap(Fc)-Aib-L-Dap(Fc)-Aib-Aib-NH-iPr, were investigated by X-ray diffraction, 2D-NMR, CD and IR spectroscopies. Due to the helical conformation, in Z-Aib-L-Dap(Fc)-Aib-Aib-L-Dap(Fc)-Aib-NH-iPr, the Fc groups are located on the same face of the helix, but in Z-Aib-L-Dap(Fc)-Aib-L-Dap(Fc)-Aib-Aib-NH-iPr, they are located on opposite faces. Surprisingly, two bands were found through DPV for Z-Aib-L-Dap(Fc)-Aib-L-Dap(Fc)-Aib-Aib-NH-iPr, indicating an electrostatic interaction between the Fc groups despite their longer reciprocal distance with respect to that in Z-Aib-L-Dap(Fc)-Aib-Aib-L-Dap(Fc)-Aib-NH-iPr. CD experiments at different concentrations evidenced aggregation for Z-Aib-L-Dap(Fc)-Aib-L-Dap(Fc)-Aib-Aib-NH-iPr, even at high dilutions, thus suggesting that the Fc-Fc electrostatic interaction could be of an intermolecular nature.

The results of classifying into various types the 68 examples of isolated α-turns in the X-ray diffraction crystal structures of peptides documented in the literature are presented and discussed in this review article. α-Turns characterized by the trans disposition of all ω torsion angles are common for the backbone linear peptides investigated. In contrast, the cis arrangement of the N-terminal (ωi + 1 ) torsion angle, among those generated by the three residues internal to the α-turn, is a peculiar feature of 65% of the cyclic peptides. Among linear and cyclic peptides featuring the all-trans disposition of the ω torsion angles, only one third of the α-turns display φ,ψ values not too far from those characterizing regular α-helices. In general, our findings, taken together, suggest that a significant conformational diversity is compatible with the formation of an intramolecularly H-bonded C13 -member pseudocycle (α-turn) in linear and cyclic peptides.

Despite the fact that peptide conjugates with a pendant ferrocenyl (Fc) have been widely investigated, bis-ferrocenyl end-capped peptides are rarely synthetized. In this paper, in addition to the full characterization of the Fc-CO-[L-Dap(Boc)]n-NH-Fc series, we report a comparison of the three series of bis-ferrocenyl homopeptides synthesized to date, to gain insights into the influence of α-amino isobutyric (Aib), 2,3-diamino propionic (Dap) and Cα,β-didehydroalanine (ΔAla) amino acids on the peptide secondary structure and on the ferrocene redox properties. The results obtained by 2D NMR analysis and X-ray crystal structures, and further supported by electrochemical data, evidence different behaviors depending on the nature of the amino acid; that is, the formation of 310-helices or fully extended (2.05-helix) structures. In these foldamers, the orientation of the carbonyl groups in the peptide helix yields a macrodipole with the positive pole on the N-terminal amino acid and the negative pole on the C-terminal amino acid, so that oxidation of the Fc moieties takes place more or less easily depending on the orientation of the macrodipole moment as the peptide chain grows. Conversely, the fully extended conformation adopted by ΔAla flat peptides neither generates a macrodipole nor affects Fc oxidation. The utilization as electrochemical and optical (Circular Dichroism) probes of the two terminal Fc groups, bound to the same peptide chain, makes it possible to study the end-to-end effects of the positive charges produced by single and double oxidations, and to evidence the presence “exciton-coupled” CD among the two intramolecularly interacting Fc groups of the L-Dap(Boc) series.

The foldamer field is continuously expanding as it allows to produce molecules endowed with 3D-structures and functions never observed in nature. We synthesized flat foldamers based on the natural, but non-coded, Cα,β -didehydroalanine α-amino acid, and covalently linked to them two ferrocene (Fc) moieties, as redox probes. These conjugates retain the flat and extended conformation of the 2.05 -helix, both in solution and in the crystal state (X-ray diffraction). Cyclic voltammetry measurements agree with the adoption of the 2.05 -helix, characterized by a negligible dipole moment. Thus, elongated α-peptide stretches of this type are insulators rather than charge conductors, the latter being constituted by peptide α-helices. Also, our homo-tetrapeptide has a N-to-C length of about 18.2 Å, almost double than that (9.7 Å) of an α-helical α-tetrapeptide.

Proteins reconfigure their 3D-structure, and consequently their function, under the control of specific molecular interactions that sense, process and transmit information from the surrounding environment. When this fundamental process is hampered, many pathologies occur as in the case of protein misfolding diseases. In this work, we follow the early steps of α-synuclein (aS) aggregation, a process associated with Parkinson's disease etiopathogenesis, that is promptly promoted by a light-mediated binding between the protein and a photoactive foldamer. The latter can switch between two conformations, one of which generates supramolecular fibrillar seeds that act as molecular templates able to induce a fast β-sheet transition for aS monomers that successively undergo fibrillar polymerization. The proposed method represents a powerful tool to study protein aggregation relevant to misfolding diseases in a controlled and inducible system.

In this work, we studied and discussed a relevant aspect of peptide science, strictly related to the scientific production of Prof. Louis A. Carpino who passed away in early 2019. Specifically, we carried out a statistical survey on the significant 3D-structural parameters (bond lengths, bond angles, and torsion angles) of the currently extensively used 9-fluorenylmethyloxycarbonyl (Fmoc) a-amino protecting group introduced by Carpino in peptide synthesis. In this compilation, we considered all 131 X-ray diffraction structures available in the literature on amino acid / linear peptide derivatives and Fmoc-labeled amines. Both Fmoc secondary and tertiary urethane functionalities were examined and separately analyzed.

Peptides are well-known to play a fundamental therapeutic role and to represent building blocks for numerous useful biomaterials. Stabilizing their active 3D-structure by appropriate modifications remains, however, a challenge. In this study, we have expanded the available literature information on the conformational propensities of a promising backbone change of a terminally blocked δ-amino acid residue, a dipeptide mimic, by replacing its central amide moiety with an (E) Cβ═Cγ alkene unit. Specifically, we have examined by DFT calculations, X-ray diffraction in the crystalline state, and FT-IR absorption/NMR spectroscopies in solution the extended vs folded preferences of analogues of this prototype system either unmodified or possessing single or multiple methyl group substituents on each of its four −CH2-CH═CH-CH2– main-chain carbon atoms. The theoretical and experimental results obtained clearly point to the conclusion that increasing the number of adequately positioned methylations will enhance the preference of the original sequence to fold, thus opening interesting perspectives in the design of conformationally constrained peptidomimetics.

The unique abilities of homo-oligo-adamantyl peptides to adopt α- and γ-turn conformations are demonstrated by X-ray diffraction, and NMR and FT-IR absorption spectroscopies.

α-Amino acid residues with a ϕ,ψ constrained conformation are known to significantly bias the peptide backbone 3D structure. An intriguing member of this class of compounds is (αMe)Aze, characterized by an Nα -alkylated four-membered ring and Cα -methylation. We have already reported that (S)-(αMe)Aze, when followed by (S)-Ala in the homochiral dipeptide sequential motif -(S)-(αMe)Aze-(S)-Ala-, tends to generate the unprecedented γ-bend ribbon conformation, as formation of a regular, fully intramolecularly H-bonded γ-helix is precluded, due to the occurrence of a tertiary amide bond every two residues. In this work, we have expanded this study to the preparation and 3D structural analysis of the heterochiral (S)-Ala/(R)-(αMe)Aze sequential peptides from dimer to hexamer. Our conformational results show that members of this series may fold in type-II β-turns or in γ-turns depending on the experimental conditions.

Systems in which an external stimulus elicits a response through some sort of modification at the molecular or supramolecular level bear potential for the development of smart materials and devices. This work describes a versatile synthetic approach suitable for the stepwise incorporation of multiple, even consecutive, units of the simplest Cα,β-unsaturated β-amino acid, (E/Z)-3-aminoprop-2-enoic acid, in peptide-based foldamers. The properties of these, including photoinduced E/Z isomerizations, were investigated.

The bis‐functionalized diamondoid α‐amino acid 2‐aminoadamantane‐2‐carboxylic acid (Adm) has been used as the building block of four Nα‐formyl homo‐dipeptide alkylamide sequences via a solution‐phase Ugi multicomponent reaction approach. The conformers of these peptides have been determined in the crystalline state by X‐ray diffraction to distinguish the influences of the C‐terminal substituent. One of the Adm peptides folds into an open and a hydrogen‐bonded γ‐turn geometry. Moreover, 3D‐structures have been observed featuring two consecutive γ‐turns in an incipient γ‐helical structure, a significantly distorted nonhelical β‐turn, as well as an S‐shaped conformation with opposite helical screw senses. A significant topological variety is thus exhibited by the ‐Adm‐Adm‐ sequences contingent on their C‐terminal substituents, illustrating both the broad conformational potential and the need for further characterization of this sterically bulky residue in explorations of its ϕ, ψ space.

The influence of conformational dynamics on the self-assembly process of a conformationally constrained analogue of the natural antimicrobial peptide Trichogin GA IV was analysed by spectroscopic methods, microscopy imaging at nanometre resolution, and molecular dynamics simulations. The formation of peptide films at the air/water interface and their deposition on a graphite or a mica substrate were investigated. A combination of experimental evidence with molecular dynamics simulation was used to demonstrate that only the fully developed helical structure of the analogue promotes formation of ordered aggregates that nucleate the growth of micrometric rods, which give rise to homogenous coating over wide regions of the hydrophilic mica. This work proves the influence of helix flexibility on peptide self-organization and orientation on surfaces, key steps in the design of bioinspired organic/inorganic hybrid materials.