Tuning foldable building blocks using sulfur – TUNIFOLD-S

The originality of the project, which unites organic chemists, gas phase and condensed spectroscopists and theoretical chemists, lies in the unique combination of (a) the exploitation of the specific properties of sulfur for the fine tuning of non-covalent interactions in foldamer manifolds; (b) the characterization of foldamer model conformations using conformer-selective spectroscopic gas phase techniques, which is still highly unusual in the foldamer field, as well as vibrational circular dichroism in solution; and (c) the role of theory for guidance during the selection of appropriate building blocks.

Four elementary building-blocks, all based on alpha-amino acids with a sulfur atom in position gamma, one non-cyclic (S-methylcytosine) and the following three cyclic (G, Y, Z), with 4- , 5- and 6-membered side chains respectively, were synthesized and then characterized by gas phase laser spectroscopy associated with detailed quantum chemistry calculations. These studies have demonstrated the presence of NH-S hydrogen bonds, whose spectral signature in the NH stretching region is specifically red-shifted, and the preference of these blocks to form intraresidue NH-S bonds, leading to 6-membered rings. The conformational landscapes of A and G being very different, with the existence (A) or absence (G) of competition with other types of H bond, different behaviors are expected in AA and GG dimers and oligomers.
Synthesis of dimers (AA and GG) has been launched

The library of building blocks is been extended. Dimer is synthesis is been pursuited

The analysis of the H-bonding pattern is in progress in a series of dimers.

The synthesis of larger oligomers will be launched during the third year of the project.

The synthesis procedure of cyclic building blocks has been presented as an oral communication in two meetings.

A first publication focusing on the formation of 6-membered ring NH-S H-bonds
is in project.

Networks of regular non-covalent interactions have been the cornerstone of the emerging science of foldamers, which are defined as synthetic oligomers that adopt well-defined portfolios of folded shapes, amongst which helices are the most prevalent. Peptidomimetic foldamers endeavor to recreate the topology of helical segments of natural peptides, notably in terms of displaying hot-spot side chains, and benefit from being resistant to proteolysis. Other foldamers are proposed to serve as templates or hosts for small molecules and can be signal-responsive, making them of interest for molecular recognition, transport or encapsulation. However, a limiting factor in contemporary foldamer design concepts is that the non-covalent interactions which have been exploited so far are largely dependent on amide-type NH···O=C hydrogen bonds. Other types of non-covalent interactions are much rarer, and short-range NH···S hydrogen bonds in particular have never been systematically integrated as design features for foldable peptidomimetic molecular architectures.
The objective of this project is to examine specific foldamer building blocks having a built-in 5-membered-ring NH···S hydrogen bond feature and to explore their ability to promote new folding patterns in backbones which do not normally fold, or to promote alternative folding propensities in dimers or small oligomers. We intend to establish and test predictive rules for unprecedented peptidic foldamer design principles based on these NH···S hydrogen bond interactions. A central feature of the project will be the identification and characterization of each contributing conformer within in a set of conformers for a given molecular system, an objective which cannot be achieved satisfactorily using the conformational analysis techniques habitually employed by foldamer chemists, because those techniques provide data which is an average of all the contributing conformers.

The novelty of the project lies in the unique combination of (a) the proposed exploitation of the specific properties of sulfur for the fine tuning of non-covalent interactions in foldamer manifolds; (b) the gas phase characterization of foldamer model conformations, which is still highly unusual in the foldamer field; and (c) the role of theory for guidance during the selection of appropriate building blocks.

The proposed strategy is as follows:
i) Firstly, a library of ten monomer systems in which an intra-residue NH···S hydrogen bond can be formed will be tested through an in silico screening based on the theoretical exploration (force-field then quantum chemistry level) of the conformational landscape of the library systems. This should orient and focus the synthetic work on those building blocks exhibiting new interactions, in particular intra-residue 5-membered ring NH···S hydrogen bond.

ii) Secondly, the formation of short range intra-residue interactions and the way these are challenged by longer range inter-residue interactions will be assessed experimentally in monomers and then in dimers. For this purpose the building blocks selected from the in silico screening will be synthesized and fully characterized by conformer-selective laser spectroscopy in the gas phase and vibrational circular dichroism (VCD) in the condensed phase. The experimental studies will be supported by quantum chemistry calculations conducted in parallel.

iii) Finally, as a concept test, the model systems which provide the most promising results in terms of control of conformational populations will be retained for inclusion in short oligomers up to 5 residues. These compounds will be synthesized and studied in solution using standard characterization tools as well as VCD.

Following this strategy, it is expected that new classes of foldamer manifolds or folding patterns featuring NH···S hydrogen bond interactions will be revealed, helping foldamer scientists to advance beyond the current inventory of mainly helical topographies.