Conformational Analysis of a Stereochemically Complete Set of Cis-enediol Peptide Analogues

A conformational analysis of a stereochemically complete set of peptide analogues based on a
cis-enediol unit is presented. The cis-enediol unit, which can replace a two or a three amino acid segment
of a peptide, contains two “side chains”, four asymmetrical carbon atoms, and six free dihedral angles. To
determine the accessible conformational space, the molecules are divided into three fragments, each
containing two free dihedral angles. The energy surfaces are computed for all dihedral angle values, and
the possible conformations of the cis-enediol unit analogues are built using all combinations of the surface
minima. Such a “build-up” procedure, which is very fast, is able to reproduce 75% of the minima obtained
from a full dihedral angle exploration of the conformational space. The cis-enediol unit minima are compared
with the corresponding di- and tripeptide minima; all peptide minima can be closely matched by a cis-enediol unit minimum of low energy (less than 2.2 kcal/mol above the lowest energy conformer). However,
there are low energy minima of the cis-enediol unit that have no corresponding minima in peptides. The
results are shown to depend strongly on the chirality of the analogues. The ability of each of the
stereoisomers to mimic natural peptides, evaluated by the present approach, is correlated with its
experimental activity in a renin inhibition assay.