Design of Cyclic Peptides - Peptide and Protein Design for Biopharmaceutical Applications - page 149

contribution to the formation of a specific conformation is small
[101,104]. Turns in small peptides are mainly determined by steric
effects [104]. The stability of the hydrogen bonds is also very sensitive
to the surrounding medium. Interaction of peptide bonds with a polar
medium can easily break internal hydrogen bonds, while in nonpolar
media, like membranes or lipophilic organic solvents, hydrogen bonds
can actually impose constraints on the conformational freedom of
cyclized peptides.

4.3.3 Flexibility of Cyclized Scaffolds

Compared to linear template structures, cyclic peptides differ not only in
structural characteristics but also in displaying a modified dynamical
behaviour. Since, in particular, backbone flexibility seems to play an
important role for cellular uptake (bioavailability), the dynamics of cyclic
peptides and the differences in relation to the linear precursor are treated
below.

4.3.3.1 Backbone dynamics

Linear peptides intrinsically have several degrees of freedom. As has
already been explained, even small compounds can adopt thousands of
different conformations. These structures, however, cannot directly be
observed, by NMR spectroscopy for example, because they are in fast
exchange. Only in cases where stable secondary structural elements in
slow exchange are formed, more than one conformation is detectable
via NMR. To drastically reduce fast dynamics, head-to-tail cyclization
is a particularly suitable method. The main effect of ring closure is
visible when analysing the dynamical behaviour of the peptide back-
bone. Here, most of the degrees of freedom are frozen, resulting in a
more or less rigid conformation. If there are more structural arrange-
ments that are separated by a high-energy barrier, several signal sets
will appear in the NMR spectrum. At this point, however, it should be
explicitly noted that there are still dynamics left; in particular, synchro-
nous dihedral bond flips about both adjacent single bonds flanking a
peptide bond (f and c) are found. These motions are usually fast on the
NMR time scale, thus only one signal set is observed. This example
clearly demonstrates that it is not mandatory for conformational pre-
ference to be accompanied by complete rigidity of the peptide