Molecules & Biomolecules.

The conformational behaviour of amino acids is of critical interest to understand the dynamical role of these molecules in protein or polypeptide formation. Consequently, extensive structural research has been conducted on amino acids in their natural solid-state phase. However, in the solid state amino acids present a zwitterionic structure (i.e. a bipolar, ionized form of the type +H3N-CH(R)-COO-), which does not occur in the polypeptide chain. In peptides and proteins amino acids participate in their neutral forms. To obtain the structure of the neutral amino acids research should be conducted in the gas phase, in an atmosphere that is essentially free of intermolecular interactions with other partners. In particular, the collisionless environment of a supersonic jet seems particularly well suited for such studies. Rotational spectroscopy is the only technique that, thanks to its inherently superior resolution, can distinguish unambiguously between different isomers, conformers, or isotopomers and provide accurate structural information directly comparable to the in vacuo theoretical predictions.

Tautomerism in Neutral Histidine, Angew.
Chem. Int. Ed. 2014, 53, 11015-11018

Histidine is an important natural amino acid, involved in many relevant biological processes, which, because of its physical properties, proved difficult to characterize experimentally in its neutral form. In this work, neutral histidine has been generated in the gas phase by laser ablation of solid samples and its NεH tautomeric form unraveled through its rotational spectrum. The quadrupole hyperfine structure, arising from the existing three ¹⁴N nuclei, constituted a site-specifically probe for revealing the tautomeric form as well as the side chain configuration of this proteogenic amino acid.

Carbohydrates are one of the most versatile biochemical building blocks, widely acting in energetic, structural, or recognition processes. The importance of its structure has been the driving force behind the development of methods for elucidating the shape of their building blocks, monosaccharides. Thus, it comes as no surprise that 3D structures and relative stability of conformers of monosaccharides continue to be an area of great research interest. The subtle variation in hydroxyl arrangement is thought to account for differences in chemical and physical properties of the sugars. This is also relevant to distinguish between different conformers. Additionally, monosaccharides are also of interest in the field of astrophysics. The availability of rotational data has been the main bottleneck for examining the presence of these building blocks in the interstellar medium (ISM). Based on the rotational spectra identification, the simplest C2 sugar of glycolaldehyde has been identified, but has yet to detect the C3 sugar of glyceraldehyde. The experimental results obtained in condensed phases seem to indicate that a subtle balance between intrinsic and environmental effects governs the conformational preferences of monosaccharides; 

Sweet Structural Signatures Unveiled in Ketohexoses
C. Bermúdez, I. Peña, S. Mata, J. L. Alonso
Chem. Eur. J. 2016, 22, accepted (COVER)

The conformational behaviour of naturally occurring ketohexoses has been revealed in a supersonic expansion by Fourier transform microwave spectroscopy coupled with a laser ablation source. Three, two and one conformers of D-tagatose, D-psicose and L-sorbose, respectively, have been identified by their rotational constants extracted from the analysis of the spectra.

Singular structural signatures involving the hydroxyl groups OH(1) and OH(2) have been disentangled from the intricate intramolecular hydrogen bond networks stabilising the most abundant conformers. The present results place the old Shallenberg and Kier sweetness theories on a firmer footing.

Structural signatures for exo-anomeric effect have been extracted from the archetypal methyl-β-D-xyloside using broadband Fourier transform microwave spectroscopy combined with laser ablation. Spectrum analysis allows the determination of a set of rotational constants, which has been unequivocally attributed to conformer cc-β-4C1 g−, corresponding to the global minimum of the potential energy surface, where the aglycon residue (CH3) orientation contributes to maximization of the exo-anomeric effect. Further analysis allowed the determination of the rs structure, based on the detection of 11 isotopologues-derived from the presence of six 13C and five 18O atoms-observed in their natural abundances. The observed glycosidic C1−O1 bond length decrease (1.38 Å) can be interpreted in terms of the exo-anomeric effect. As such, the exo-anomeric effect presents itself as one of the main driving forces controlling the shape of many biologically important oligosaccharides.

The conformational behaviour of isolated D-glucose has been revealed in this work using Fourier transform microwave spectroscopy coupled with laser ablation of crystalline α- and β-glucopyranose samples. Four conformers of α-D-glucopyranose and three of β-D-glucopyranose have been unequivocally identified on the basis of the spectroscopic rotational parameters in conjunction with ab initio predictions.

Stereoelectronic hyperconjugative factors, like those associated with anomeric or gauche effects, as well as the cooperative OHO chains extended along the entire molecule, are the main factors driving the conformational behaviour. The most abundant conformers exhibit a counter-clockwise arrangement (cc) of the network of intramolecular hydrogen bonds.

*The shape of D-glucosamine,
Phys. Chem. Chem. Phys., 2014, 16, 23244-23250

*Erythrose revealed as furanose forms,
Chem.Commun., 2013, 49, 10826-10828

*Six Pyranoside Forms of Free 2-Deoxy-D-ribose,
Angew. Chem. Int. Ed., 2013, 52, 11840-11845

Neurotransmitters are substances produced and secreted by a neuron to cross the synapse space between neurons. They comprise several different families of compounds, including amino acids, peptides, and biogenic amines. A key structural feature of neurotransmitters is their high conformational flexibility. This dictates molecular shape, which, in turn, has a great influence on both transport properties and molecular recognition processes at the receptor site. The study of the intricate processes of neurotransmission at the molecular level and the interactions of neurotransmitters under complex biological conditions must be preceded by detailed characterization of the conformational properties of the neurotransmitters in the absence of intermolecular interactions, thus avoiding alterations of their intrinsic structural preferences, matching the conditions found in the gas phase.

Seven Conformers of Neutral Dopamine Revealed in the Gas Phase,
J. Phys. Chem. Lett., 2013, 4, 486-490

The rotational spectrum of neutral dopamine has been investigated for the first time using a combination of Fourier transform microwave spectroscopy with laser ablation. The parameters extracted from the analysis of the spectrum unequivocally identify the existence of seven conformers of dopamine. ¹⁴N nuclear quadrupole coupling interactions have been used to determine the orientation of the amino group probing the existence of stabilizing N–H···π interactions for all observed conformers.

Much effort has been devoted to the identification of preferred tautomers of nucleobases since the structure of nucleic acids and its base pairs were first reported. The best experimental approach to address the structural preferences of nucleobases is to place them under isolation conditions in the gas phase, cooled in a supersonic expansion. Under these conditions, the various tautomers/conformers can coexist and are not affected by the bulk effects of their native environments, which normally mask their intrinsic molecular properties. The main restriction to the gas-phase study of these building blocks is the difficulty in their vaporization owing to their high melting points (ranging from 316 ºC for guanine to 365 ºC for adenine) and associated low vapor pressures.

All Five Forms of Cytosine Revealed in the Gas Phase,
Angew. Chem. 2013, 125, 2387-2390

Give me five! All five tautomers and conformers of cytosine were characterized in the gas phase by laser ablation molecular beam Fourier transform microwave spectroscopy. The spectra were assigned unambiguously on the basis of the hyperfine structure due to the three ¹⁴N nuclei (see picture; N blue, O red). The relative energies of the identified species were estimated from the relative intensities of the spectra.