Metallopeptides
COMMUNICATION
ligand ratios progressively shifts the equilibrium towards the
expected 1:1 complex later in the titration (Figure 1).
ral residues, we designed and applied a first-principle proto-
col instead of utilizing the recently reported knowledge-
[22]
driven and fragment-based approaches. Calculations were
first undertaken to characterize the conformational space of
the isolated ligands. Large torsional Monte Carlo samplings
coupled with low-energy mode displacements were carried
[23]
out for both d- and l-Pro species. In each case, about 250
minima were identified within
a
window of about
À1
2
1 kJmol . The conformers presented similar overall ten-
dencies in both ensembles, and could be clustered into a re-
duced number of folds. In most, substantial p–p interactions
between the two Bpy units were observed (see Figure S1 in
the Supporting Information), and the lowest energy confor-
mations presented stronger stacking. Despite some variabili-
1
2
ty, the Gly -Pro-Gly loop mainly adopts a turn with a hydro-
gen bond between the carbonyl of the proline and the nitro-
2
gen of the Gly backbone elements. Importantly, the asym-
3
Figure 1. UV/Vis titration of 13 mm l-P with increasing concentrations of
II
metry arising from the d-Pro and l-Pro residues appears in
the lowest energy conformations as a loop in an anticlock-
wise configuration for the former and a clockwise configura-
tion for the latter.
Co and best fit to a mixed 1:1 and 1:2 model (solid line). Curves repre-
senting the relative populations of free l-P (L), ML and ML
3
2
complexes
are overlaid as dashed lines.
II
The structures of the Zn complexes were obtained by
II
II
The thermodynamic stabilities of the Ni and Zn com-
plexes of l-P are about one order of magnitude less stable
a constrained minimization of the lowest-energy conforma-
tion of the isolated ligands towards a tetrahedral geometry
3
II
4
[24]
than the Co equivalent (log b ꢀ6.75–6.08). The l-P metal
of the nitrogen atoms in the bipyridine groups, followed
1
1
3
complexes appear only marginally less stable than their l-P
by a Quantum Mechanical/Molecular Mechanics minimiza-
tion of the zinc-bound complexes (see the Supporting Infor-
5
analogues but, in contrast, all of the l-P metallopeptides
display significantly lower binding constants (log b ꢀ5.18–
[25]
mation) by using the ONIOM scheme, as implemented in
1
1
5
[26]
3
.33). Moreover, the titration profiles of the l-P peptides
Gaussian 09. In all of the resulting structures, the p–p in-
suggest the occurrence of higher order species and/or oligo-
mers. Finally, in addition to these titrations, the absence of
teractions have been lost, so that the two Bpy units are
1
2
almost perpendicular, the twist of the Gly -Pro-Gly loop
3
2
d–d transition bands in concentrated solutions of l-P with
has been amplified, and the Pro–Gly hydrogen bonding has
II
II
Ni and Co suggests that these metals adopt an octahedral
configuration, completing their coordination sphere with
been significantly lost. Importantly, the optimized structures
of the d-Pro and l-Pro systems appear to be highly symmet-
ric, with the metal center providing them with R and S chir-
ality, respectively (Figure 2). Moreover, attempts to obtain
the inverted metal configurations based on alternative low-
energy conformations of the ligand were unsuccessful in all
cases.
3
2+
two water molecules, that is, as [M
ACHTUNGTNRENUNG( l-P ) ACTHUNGTRENNU(GN H O) ] species.
2 2
Given the renewed significance of chiral coordination
[5]
complexes with biological applications, we were thus par-
ticularly interested in the effect of the chiral d-Pro and l-
Pro residues included in the peptide loops. Considering that
3
4
l-P and l-P form coordination compounds of similar ther-
Further comparisons between the free and metal-bound
systems show that the conformations adopted by the ligands
in the complexes are relatively close to those of the free li-
modynamic stabilities, we decided to focus our attention on
3
the l-P peptide because the shorter three amino acid loop
À1
in this ligand should impose tighter conformational restric-
gands in the 21 kJmol window from the absolute minima
4
tions than l-P , and hence provide better chiral induction in
(with a root-mean-square deviation (RMSD) below 1 ꢆ).
The conformational transition of the ligands between un-
bound and bound structures only requires the rearrange-
ment of one of the Bpy units, for which the twist of the loop
is accentuated (Figure S1 in the Supporting Information).
Our results show that the chirality of the Pro residue dic-
tates a highly asymmetric conformational space for the li-
gands. This leads to the preorganization of the ligands to-
wards conformations that appear to condition the chirality
the resulting metallopeptides.
At this point, we decided to carry out molecular modeling
studies to gain some insight into the structural features of
3
2+
the [Zn
ACHTUNGTRENNUNG( l/d-P )] complexes and identify the relationship
between the chirality of the proline residue and that of the
[20]
resulting metal complex. It must be noted that the model-
ing of metal-mediated recognition processes is still one of
[21]
the major challenges faced by computational chemistry,
[
27]
and there are no reports of reliable models of metal com-
plexes derived from highly flexible ligands, a tool which
could be very useful in metallo-supramolecular chemistry
and inorganic chemical biology. To determine the structure
of both complexes, and because of the presence of non-natu-
of the metal-bound systems.
II
Zn complexes are diamagnetic and thus suitable for
NMR studies. This allowed us to make a complete NMR
3
2+
characterization of [Zn
ACHTUNGTRNENUNG( l-P )] to validate in solution the
3
structure described above. First, the isolated ligand (l-P )
Chem. Eur. J. 2012, 00, 0 – 0
ꢅ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
3
&
ÞÞ
These are not the final page numbers!
Rama, Gustavo
