Combining laser desorption with a supersonic expansion together with the selectivity of IR/UV double resonance spectroscopy makes it possible to isolate and characterise the gas phase of remarkable backbone conformations of short peptide chains mimicking protein segments. A systematic bottom-up approach involving a conformer-specific IR study of peptide sequences of increasing sizes has enabled us to map the spectral signatures of the intramolecular interactions, which shape the peptide backbone, in particular H-bonds. The precise data collected are directly comparable to the most sophisticated quantum chemistry calculations of these species and therefore constitute a stringent test for the theoretical methods used. One-residue chains reveal the local conformational preference of the backbone and its dependence upon the nature of the residue. The investigation of longer chains provides evidence for a competition between simple successions of local conformational preferences along the chain and more folded structures, in which a new H-bonding network, involving distant H-bonding sites along the backbone, takes place. From three residues, the issue of helical folding can also be addressed. The present review of the gas phase literature data emphasizes the observation of remarkable secondary structures of biology, including short segments of beta-strands, gamma- and beta-turns, combinations of turns, including a 3(10) helix. It also provides evidence for the flexibility of the peptide chains, i.e., a critical influence of rather minor interactions (like side-chain/backbone interactions) on the conformational stability. Finally, the paper will discuss future promising directions of the present approach.

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The conformational structure of short peptide chains in the gas phase is studied by laser spectroscopy of a series of protected dipeptides, Ac-Xxx-Phe-NH 2 , XxxϭGly, Ala, and Val. The combination of laser desorption with supersonic expansion enables us to vaporize the peptide molecules and cool them internally; IR/UV double resonance spectroscopy in comparison to density functional theory calculations on Ac-Gly-Phe-NH 2 permits us to identify and characterize the conformers populated in the supersonic expansion. Two main conformations, corresponding to secondary structures of proteins, are found to compete in the present experiments. One is composed of a doubly ␥-fold corresponding to the 2 7 ribbon structure. Topologically, this motif is very close to a ␤-strand backbone conformation. The second conformation observed is the ␤-turn, responsible for the chain reversal in proteins. It is characterized by a relatively weak hydrogen bond linking remote NH and CO groups of the molecule and leading to a ten-membered ring. The present gas phase experiment illustrates the intrinsic folding properties of the peptide chain and the robustness of the ␤-turn structure, even in the absence of a solvent. The ␤-turn population is found to vary significantly with the residues within the sequence; the Ac-Val-Phe-NH 2 peptide, with its two bulky side chains, exhibits the largest ␤-turn population. This suggests that the intrinsic stabilities of the 2 7 ribbon and the ␤-turn are very similar and that weakly polar interactions occurring between side chains can be a decisive factor capable of controlling the secondary structure.

Laser desorption of model peptides coupled to laser spectroscopic techniques enables the gas-phase observation of genuine secondary structures of biology. Spectroscopic evidence for the formation of beta-turns in gas-phase peptide chains containing glycine and phenylalanine residues establishes the intrinsic stability of these forms and their ability to compete with other stable structures. The precise characterization of local minima on the potential energy surface from IR spectroscopy constitutes an acute assessment for the state-of-the-art quantum mechanical calculations also presented. The observation of different types of beta-turns depending upon the residue order within the sequence is found to be consistent with the residue propensities in beta-turns of proteins, which suggests that the prevalence of glycine in type II and II' turns stems essentially from an energetic origin, already at play under isolated conditions.

The conformations of laser-desorbed jet-cooled short peptide chains Ac-Phe-Xxx-NH2 (Xxx=Gly, Ala, Val, and Pro) have been investigated by IR/UV double resonance spectroscopy and density-functional-theory (DFT) quantum chemistry calculations. Singly gamma-folded backbone conformations (betaL-gamma) are systematically observed as the most stable conformers, showing that in these two-residue peptide chains, the local conformational preference of each residue is retained (betaL for Phe and gamma turn for Xxx). Besides, beta turns are also spontaneously formed but appear as minor conformers. The theoretical analysis suggests negligible inter-residue interactions of the main conformers, which enables us to consider these species as good models of gamma turns. In the case of valine, two similar types of gamma turns, differing by the strength of their hydrogen bond, have been found both experimentally and theoretically. This observation provides evidence for a strong flexibility of the peptide chain, whose minimum-energy structures are controlled by side-chain/backbone interactions. The qualitative conformational difference between the present species and the reversed sequence Ac-Xxx-Phe-NH2 is also discussed.

The first spectroscopic evidence for the gas-phase formation of helical structures in short peptide chains is reported, using the IR-UV double resonance technique and DFT quantum chemistry calculations. The study involves three chemically protected peptides, all based on the same Ac-(Ala)3-NH2, (Ac = acetyl, Ala = alanine) tripeptide, in which one of the Ala residues is substituted by the aromatic phenylalanine residue. For the three molecules, only one main conformer is observed in the supersonic expansion. IR analysis shows that the structure of this conformer is strongly dependent upon the substitution site: the helical 310-type structure is observed only when Phe occupies the central residue of the chain. The present work also emphasizes that the 310-helix formation does compete with other archetypal H-bonding patterns, such as 27-ribbon or mixed structures, whose relative energetics can be greatly influenced by a modest NH-aromatic interaction.

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gamma-Turn, the shortest secondary structure of peptides, exists as two helical forms gamma(l) and gamma(d) of opposite handedness. The present gas phase study of capped l-Phe-Xxx peptides (Xxx = l-Ala, d-Ala or Aib: aminoisobutyric acid) provides a unique example of intramolecular chiral recognition of the gamma-turn helicity on Ala or Aib by the neighbouring residue Phe within the chain. With the chiral l- or d-Ala residues, the presence of a side-chain operates a discrimination between the two helical forms: one of them is widely favoured over the other (gamma(l) or gamma(d), respectively). This enables us to validate and calibrate the recognition capabilities of the nearby l-Phe residue. The discriminating interactions have been precisely characterized from their spectroscopic UV and IR signatures and identified by comparison with quantum chemistry calculations. Then, in the case of the non-chiral residue Aib, the two helical forms of the gamma-turn, which are simultaneously observed in the jet, have been discriminated and assigned by comparison with the chiral residues. The relative abundances of the diastereomeric forms l-Phe-Aib(gamma(l)) and l-Phe-Aib(gamma(d)) enable us to determine the most efficient recognition configuration.