Secondary Structure of
Short β‑Peptides
as the Chiral Expression of Monomeric Building Units: A Rational and
Predictive Model
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Abstract
Chirality of the monomeric residues controls and determines
the
prevalent folding of small oligopeptides (from di- to tetramers) composed
of 2-aminocyclobutane-1-carboxylic acid (ACBA) derivatives with the
same or different absolute and relative configuration. The <i>cis</i>-form of the monomeric ACBA gives rise to two conformers,
namely, Z6 and Z8, while the <i>trans</i>-form manifests
uniquely as an H8 structure. By combining these subunits in oligo-
and polypeptides, their local structural preference remains, thus
allowing the rational design of new short foldamers. A lego-type molecular
architecture evolves; the overall look depends only on the conformational
properties of the structural building units. A versatile and efficient
method to predict the backbone folds of designed cyclobutane β-peptides
is based on QM calculations. Predictions are corroborated by high-resolution
NMR studies on selected stereoisomers, most of them being new foldamers
that have been synthesized and characterized for the first time. Thus,
the chiral expression of monomeric building units results in the defined
secondary structures of small oligomers. As a result of this study,
a new set of chirality controlled foldamers is provided to probe as
biocompatible biopolymers