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.
Laboratoire Interactions, Dynamique, Laser (Laboratoire public)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Institut de Chimie Moléculaire et des matériaux d'Orsay
ISMO Institut des Sciences Moléculaires d'Orsay
Laboratoire Interactions, Dynamique, Laser
Help of the ANR 401,848 euros
Beginning and duration of the scientific project: September 2017 - 36 Months