Peptide backbone folding induced by the Cα-tetrasubstituted cyclic α-amino acids 4-amino-1,2-dithiolane-4-carboxylic acid (Adt) and 1-aminocyclopentane-1-carboxylic acid (Ac5c). A joint computational and experimental study

Abstract

The conformational study of a new group of synthetic peptides containing 4-amino-1,2-dithiolane-4-carboxylic acid (Adt), a cysteine-related achiral residue, has been carried out through a joint application of computational and experimental methodologies. Molecular Dynamics simulations clearly suggest the tendency of this molecule to adopt a γ-turn conformation in vacuum and help in analyzing the complex and crucial conformational behaviour of the dithiolane ring which appears to preferentially adopt a C_s-like structure. Electronic structure calculations carried out in solution using the Density Functional Theory also indicate the preservation of the γ-like folding in apolar solvents and the helix-like one in more polar solvents. A comparison with the achiral 1-aminocycloalkane-1-carboxylic acid (Ac₅c) has been carried out using the same computational tools. NMR and IR data on dipeptide derivatives containing the Adt or Ac₅c residue show that in chloroform solution all the models prefer a γ-turn structure, centered at the cyclic residue, stabilized by an intramolecular H-bond, whereas in a more polar solvent, i.e. dimethyl sulfoxide, this folding is not maintained. The experimental conformational studies, extended to N-Boc protected tripeptides, clearly indicate the remarkable tendency of both the five-membered C^α-tetrasubstituted cyclic amino acids Adt and Ac₅c to induce the γ-turn structure also in models able to adopt the β-bend conformation.