Evidence against the hopping mechanism as an important electron transfer pathway for conformationally constrained oligopeptides

Article abstract of DOI:10.1021/ja043607e

The rate constant of intramolecular electron transfer through oligopeptides based on the α-aminoisobutyric acid residue was determined as a function of the peptide length and found to depend weakly on the donor-acceptor separation. By measuring the electr

Full text of DOI:10.1021/ja043607e

Published on Web 12/23/2004
Evidence Against the Hopping Mechanism as an Important Electron Transfer
Pathway for Conformationally Constrained Oligopeptides
Federico Polo, Sabrina Antonello, Fernando Formaggio, Claudio Toniolo, and Flavio Maran*
Dipartimento di Scienze Chimiche, UniVersita` di PadoVa, Via Marzolo 1, 35131 PadoVa, Italy
Received October 21, 2004; E-mail: f.maran@chfi.unipd.it
Scheme 1
An electron transfer (ET) between a donor (D) and an acceptor
(A) through a molecular bridge usually occurs by the superexchange
mechanism where electron tunneling occurs without transient
occupation of the states of the bridge.1 The ET may also occur by
an incoherent hopping mechanism where the bridge is more directly
involved in the process.2 This mechanism requires a thermally
activated endergonic charge injection from D to the directly
connected bridge unit. Afterward, the electron migrates through a
set of coupled units of the bridge and then an exergonic ET to A
occurs.3 For short bridges, the hopping mechanism is less efficient
than the superexchange pathway, but for longer bridges the latter
may be overwhelmed by intrabridge electron hopping. The transition
Scheme 2
is detected by observing the onset of a weak distance dependence
of the ET rate.2,4,5 This view received considerable consensus for
charge transfer across DNA strands.2,4 Despite some intriguing
results,5 however, the issue of its applicability to peptides (and
proteins), as proposed in recent studies,2,6 is not yet settled. This
communication is aimed at providing insight into this important
issue.
We have recently7 studied the electrochemically induced ET from
a phthalimide radical anion donor (formal potential, E° ∼ -1.35
V)8 to a peroxide acceptor (E° ) -1.21 V) across R-aminoisobu-
tyric acid (Aib) homooligomers of different lengths (Scheme 1:
1n). Aib oligopeptides are known to form 310-helices9 and thus, for
1n, n represents the number of the possible intramolecular
CdO‚‚‚H-N hydrogen bonds. The intramolecular ET rate was
found to depend weakly on the number of Aib units and the related
edge-to-edge D/A distance (dee); in fact, it was even found to
increase in a certain peptide length range. Although an important
bridge-length-dependent ET-mediating role of the intramolecular
hydrogen bonds was proposed as being responsible for such
unprecedented behavior,7 a hopping mechanism also could be
invoked. To address this problem, we designed another series of
compounds, 2n, aimed at assessing the feasibility of the latter
mechanism across peptides.
acceptor, and thus the electron is trapped concertedly with O-O
bond cleavage. While the reduction of peroxides has a large intrinsic
barrier and thus is very slow,11 ET to moieties such as the
p-cyanobenzamide or phthalimide group undergoes fast electrode
kinetics. Therefore, despite the unfavorable thermodynamics, the
electrode process entails electron injection into the fast end of 2n,
D, followed by slow and irreversible intramolecular ET from D to
the slow end of 2n, A.
The intramolecular rate constant (kintra) values were determined
by cyclic voltammetry (CV) in N,N-dimethylformamide (DMF).
By carrying out concentration studies and digital simulation of the
CV curves obtained with peptides 2n and corresponding model
molecules, the effect of the competitive intermolecular ET could
be determined. Figure 1 shows the observed kintra values, in
comparison with the corresponding data of the 1n series.7
There are a number of features worth noting in Figure 1. In both
cases, the rate is slightly dependent upon distance for 1 e n e 3
(dee increases by 4.0 ( 0.5 Å). For example, from 21 to 23,
log kintra decreases by only 0.43 unit, much smaller than the ∼2.3
unit decrease expected for a simple exponential decay characterized
Compounds 2n differ from 1n only by the donor that is now the
p-cyanobenzamide moiety (E° ∼ -1.70 V).8 This makes the ET
free energy (∆G°) more negative by 0.35 eV. A more powerful
donor was expected to cause two effects (Scheme 1): to increase
the rate of the superexchange ET and, particularly important, to
diminish the energy gap between the donor and the bridge, thereby
favoring the hopping mechanism relative to compounds 1n.
Compounds 2n were synthesized and characterized along similar
lines as reported for 1n.10 In keeping with the well-established
propensity of Aib oligopeptides to form rigid 310-helices,9 IR
1
by the scaling factor of R-helices, â ) 1.3 Å-1 12
. The relative rate
absorption and H NMR spectral data revealed that the onset of a
regular secondary structure in solution is already evident in the
shortest peptides, resulting in conformers whose rigidity increases
with n.
The ET between D and A was triggered electrochemically, as
illustrated in Scheme 2. The peroxide group is a dissociative-type
increase (kintra difference between the 2n and 1n series) is more
marked for the shorter compounds. Finally, the rate decrease from
n ) 3 to n ) 4 is similar for 1 and 2, which provides support that
the difference observed with the shortest peptides is real. To explain
the latter, a more pronounced relevance of the superexchange
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C O M M U N I C A T I O N S
peptides of similar lengths but composed of R-amino acids that
either lack intramolecular hydrogen bonds (oligoprolines) or require
longer main chains to originate a sufficiently stable secondary
structure (oligopeptides based on other protein amino acids), the
likeliness that a hopping mechanism would be operative appears
to be even less probable. The smooth distance dependence that we
observe with Aib oligopeptides is justified by the fact that while
addition of a new R-amino acid unit increases dee, it also lowers
the energy of the backbone and introduces new hydrogen-bond ET
shortcuts. These effects increase the overall electronic coupling
governing the ET reaction and thus would counteract the usual rate
decrease expected for the distance dependence of a superexchange
ET mechanism.
Figure 1. Dependence of the intramolecular ET rate constants for
compounds 2n (b, left scale) and 1n (O, right scale) on the number of
intramolecular hydrogen bonds. T ) 25 °C.
Acknowledgment. This work was financially supported by the
Ministero dell’Istruzione, dell’Universita` e della Ricerca (MIUR).
Supporting Information Available: Electrochemical analysis and
synthesis and characterization of the investigated peptides (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
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But does the ET entail also some hopping component? To answer
this, two quantities need to be determined or estimated: (i) the
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We focused on 23 and synthesized a model bridge, peptide 33,
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Information). A similar value, 0.37 eV, was obtained for 21. By
considering the outcome of these experiments and even by assuming
a large error for ∆E, we can conclude that the thermal population
of the bridge requires an energy that is at least twice the Ea value.
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bridge and thus favor the hopping mechanism. Nevertheless, our
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