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This research was financially supported by the NIH (grant
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Materials and Methods
11 February 2016; accepted 30 March 2016
Conformational photoswitching of a
synthetic peptide foldamer bound
within a phospholipid bilayer
Matteo De Poli,1 Wojciech Zawodny,1 Ophélie Quinonero,1 Mark Lorch,2
Simon J. Webb,1,3 Jonathan Clayden4*
The dynamic properties of foldamers, synthetic molecules that mimic folded biomolecules,
have mainly been explored in free solution. We report on the design, synthesis, and
conformational behavior of photoresponsive foldamers bound in a phospholipid bilayer
akin to a biological membrane phase. These molecules contain a chromophore, which
can be switched between two configurations by different wavelengths of light, attached
to a helical synthetic peptide that both promotes membrane insertion and communicates
conformational change along its length. Light-induced structural changes in the
chromophore are translated into global conformational changes, which are detected
by monitoring the solid-state 19F nuclear magnetic resonance signals of a remote
fluorine-containing residue located 1 to 2 nanometers away. The behavior of the foldamers
in the membrane phase is similar to that of analogous compounds in organic solvents.
In the field of synthetic biology, substantial progress has been made in the use of light o control biological function by custom- ization of membrane-bound proteins with artificial chromophores (1). In parallel, synthetic molecular photoswitches have been used
to control chemical processes such as ligand
binding and catalysis in isotropic solution (2, 3).
Here, we report the design and synthesis of a
fully synthetic photoresponsive helical molecule
that can insert into a phospholipid bilayer. We
show that light-induced switching between con-
figurational isomers can be used to induce global
conformational change that propagates over sev-
eral nanometers in a synthetic molecule within
a membrane environment. Membrane-bound
artificial photoswitchable synthetic structures
capable of translating photochemical informa-
tion into extended conformational changes, in a
manner reminiscent of the operation of natural
photoswitchable proteins such as rhodopsin (4),
could ultimately provide opportunities for con-
trolling chemical processes within membrane-
A detailed understanding of how the phospholipid bilayer affects long-range conformational changes in membrane-bound molecules
is impeded by the difficulty of directly observing
conformational changes in the membrane phase
and by a lack of examples of biomolecules that
adopt well-defined structures both in the membrane phase and in solution (5–7). A simplified
yet functional synthetic analog of the membrane-spanning domains of natural proteins, containing in-built spectroscopic handles that are diagnostic of conformation, would be a powerful tool.
Dynamic conformational changes in a membrane-bound molecule could then be explored, free of the
complexities of protein structure, and compared
with analogous changes in isotropic solution.
Given the requirement for a synthetic structure
with a tendency to embed into membranes and
with well-understood conformational dynamics,
we chose to explore the membrane insertion of
foldamers [synthetic polymeric molecules with well-
defined conformations (8)] built from oligomers
of the achiral amino acid Aib (2-aminoisobutyric
acid; Fig. 1A, shown in black). These Aib foldamers
show a strong preference for helical conforma-
tions (9) and therefore have two principal con-
formational states, in which the helix adopts a
global left- or right-handed screw sense. Fur-
thermore, helical Aib-rich peptides have a known
tendency to insert into phospholipid bilayers
because they occur naturally in the form of
membrane-disrupting fungal antibiotics known
as peptaibols (10).
A chiral amino acid residue was covalently
linked to the N terminus of an (Aib)n foldamer
and then N-acylated by an azobenzene motif
(Fig. 1A, shown in red) to enable photochemical
induction of conformational change (11). This
motif manifests well-understood photochemical
interconversion between E and Z configurations
and thus offers a reversible light-driven means
of initiating conformational reorganization from
the terminus of the oligomer. The influence of
azobenzene geometry on the relative population
of conformational states of the (Aib)n helix
was first explored in solution using foldamers
1 (Fig. 1A) that carry a C-terminal glycinamide as
a solution-state 1H nuclear magnetic resonance
(NMR)–compatible reporter of helical conforma-
tion (12). An unequal conformational population
can result when the first turn of a helical Aib-
containing foldamer incorporates a single chiral
tertiary amino acid residue, and the magnitude
of this bias depends on the detailed structure of
the first (N-terminal) b-turn of the helix (12).
1H NMR spectra of valine-containing foldamers
1a to 1d were acquired in deuterated methanol
(CD3OD) solution as their thermally equilibrated
mixtures of E (major) and Z (minor) geometrical
isomers (analogous behavior in phenylalanine-
containing foldamers is reported in table S1).
Methanol has a polarity similar to that of the
interfacial region of the phospholipid bilayer
and prevents aggregation of the foldamers in so-
lution (13, 14). Because the left- and right-handed
conformational states of an (Aib)n helix inter-
convert on a submillisecond time scale at am-
bient temperature, the 1H NMR spectrum that
is observed results from a weighted average of
both conformational states, reflecting their rel-
ative population. The diagnostic feature in the
averaged spectra of foldamers 1 is the signal
or signals due to the methylene protons of the
C-terminal glycinamide residue. A single signal
indicates equal populations of the two states; a
pair of signals indicates unequally populated
1School of Chemistry, University of Manchester, Manchester
M13 9PL, UK. 2Department of Chemistry, University of Hull,
Hull HU6 7RX, UK. 3Manchester Institute of Biotechnology,
University of Manchester, Manchester M1 7DN, UK. 4School
of Chemistry, University of Bristol, Bristol BS8 1TS, UK.
*Corresponding author. E-mail: firstname.lastname@example.org