Enzyme-Mediated Directional Transport of a Small-Molecule Walker with Chemically Identical Feet

Article abstract of DOI:10.1021/jacs.7b06503

We describe a small-molecule "walker" that uses enzyme catalysis to discriminate between the relative positions of its "feet" on a track and thereby move with net directionality. The bipedal walker has identical carboxylic acid feet, and "steps" along an isotactic hydroxyl-group-derivatized polyether track by the formation/breakage of ester linkages. Lipase AS catalyzes the selective hydrolysis of the rear foot of macrocyclized walkers (an information ratchet mechanism), the rear foot producing an (R)-stereocenter at its point of attachment to the track. If the hydrolyzed foot reattaches to the track in front of the bound foot it forms an (S)-stereocenter, which is resistant to enzymatic hydrolysis. Only macrocyclic walker-track conjugates are efficiently hydrolyzed by the enzyme, leading to high processivity of the walker movement along the track. Conventional chemical reagents promote formation of the ester bonds between the walker and the track. Iterative macrocyclization and hydrolysis reactions lead to 68% of walkers taking two steps directionally along a three-foothold track.

Full text of DOI:10.1021/jacs.7b06503

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Article
Enzyme-Mediated Directional Transport of a Small-
Molecule Walker With Chemically-Identical Feet
Christopher J. Martin, Alan T. L. Lee, Ralph W. Adams, and David A. Leigh
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 01 Aug 2017
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Enzyme-Mediated Directional Transport of a Small-Molecule
Walker With Chemically-Identical Feet
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Christopher J. Martin, Alan T. L. Lee, Ralph W. Adams and David A. Leigh*
School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, United Kingdom.
Supporting Information Placeholder
tachments (within a macrocycle) to the essentially7
prochiral footholds of an isotactic oligomer track (Figure
ABSTRACT: We describe a small-molecule ‘walker’ that
uses enzyme catalysis to discriminate between the relative
1).
positions of its ‘feet’ on a track and thereby move with net
directionality. The bipedal walker has identical carboxylic
acid feet, and ‘steps’ along an isotactic hydroxyl-group-
derivatized polyether track by the formation/breakage of
ester linkages. Lipase AS catalyzes the selective hydrolysis
of the rear foot of macrocyclized walkers (an information
ratchet mechanism), the rear foot producing an (R)-
stereocenter at its point of attachment to the track. If the
hydrolyzed foot re-attaches to the track in front of the
bound foot it forms an (S)-stereocenter, which is resistant
to enzymatic hydrolysis. Only macrocyclic walker-track
conjugates are efficiently hydrolyzed by the enzyme, lead-
ing to high processivity of the walker movement along the
track. Conventional chemical reagents promote formation
of the ester bonds between the walker and the track. Iter-
ative macrocyclization and hydrolysis reactions lead to 68
% of walkers taking two steps directionally along a three-
foothold track.
Figure 1. Directional transport of a small-molecule walker
with two chemically identical feet: I, reagent-promoted mac-
rocyclization (no selectivity in site of attachment); II, enzy-
matic hydrolysis (rear foot selectively hydrolyzed: (R-) hydro-
lyzed much faster than (S-)).
Upon macrocyclization of 1-1 (Figure 1) handedness is
induced at each site of attachment to isotactic functional
groups on the track (1,2-2). If that difference in stereo-
chemistry can be exploited to make the rear foot more
reactive to a chiral catalyst or reagent (e.g. by stereoselec-
tive hydrolysis by an enzyme; Figure 1, process II), the
rear foot should be cleaved in preference to the front foot.
The resulting open-chain species (2-1, Figure 1) is attached
to the track through one, now essentially achiral,7 at-
tachment point. Reattachment of the dangling foot of 2-1
through macrocyclization with the track (Figure 1, process
I) then forms a mixture of 1,2-2 (in which the walker has
returned to its original position on the track) and 2,3-2 (in
which the walker has taken a step forward). Crucially for
the directional walking mechanism, in 2,3-2 the foot that
was the front (unreactive) (S)-attached foot in 1,2-2 has
now become the rear (reactive) (R)-attached foot. Itera-
tive repetition of the unselective macrocyclization and
stereoselective hydrolysis steps (I, II, I, II,… etc) should
lead to directional transport of the walker with chemically
identical feet along the isotactic track (Figure 1).
INTRODUCTION
Bipedal motor proteins perform tasks in the cell by direc-
tionally ‘walking’ along microtubule tracks.1 A well-
studied example is kinesin I, a homodimeric protein with
two chemically identical ‘feet’ that typically takes 75–175
directional steps before fully detaching from the track.2
Several synthetic small-molecule walkers have been de-
veloped,3-5 however only two4 are able to walk along mo-
lecular tracks with net directionality. Both rely on the
walker having chemically distinct feet that undergo or-
thogonal chemistries with the track in order to achieve
the key property of processivity: that is to enable each
foot to remain attached to the track under conditions
where the other one moves so that the walker does not
fully detach from the track. Kinesin I uses mechanical
strain to differentiate the reactivity of its identical feet
during the walking cycle.6 We wondered if it would be
possible to achieve a similar outcome for a small-
molecule walker with two identical feet, by exploiting the
difference in stereochemistry of front and rear foot at-
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mation)—selectively hydrolyzes the ester linkage at the
RESULTS AND DISCUSSION
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(R)-stereocenter (Scheme 1a, top sequence, II) leading to
the formation of 2-1, i.e. the rear leg of the walker has
become detached from the track. At this stage the walker
has taken one step along the track (from starting position
1-1) via a passing-leg gait.
Walker and Track Design
We experimentally explored this concept with a molecu-
lar walker, 3, based on a C2-symmetric (R,R)-(+)-
hydrobenzoin motif (Scheme 1a) and a track consisting of
a poly(ethylene glycol) chain featuring an isotactic triad
of three secondary alcohol footholds at one end that can
attach to the carboxylate feet of the walker through the
formation of ester linkages. The phenyl groups of the
walker are UV-chromophores that aid analysis during
synthesis and purification. It is important that the walker
‘legs’ have the same chirality (or none) in the absence of
the track: if a meso-(R,S)-walker was used the walker-
track conjugate could potentially have differing behaviors
in the enzyme active site depending on whether the rear
leg stemmed from the (R-) or (S-) part of the hydrobenzo-
in unit. Three footholds on the track is sufficient to
demonstrate the directional transport principle aided by
unambiguous determination of the position of the walker
on the track at each stage, a feat which becomes signifi-
cantly more difficult with more than three footholds.5c,e
The polyether track confers solubility in aqueous solvents
suitable for enzymatic hydrolysis and has some flexibility
to adopt conformations that allow access to the active site
of the enzyme. The hydrolysis of chiral and prochiral
diesters by lipases generally has high substrate tolerance
and often proceeds with excellent regio- and stereochem-
ical control.8,9
Lipase AS does not hydrolyze the remaining ester linkage
in 2-1 quickly (the rate of reaction of 1,2-2 or 2,3-2 is >20x
faster than 2-1), enabling good processivity for the walk-
ing process. A second (non-directional) intramolecular
macrocyclization reaction should result in approximately
50% of the walkers forming the new positional isomer 2,3-
2 (the other 50% reforms 1,2-2). As the relative positions
of the walker’s feet change, so does the stereochemistry at
the occupied footholds; the front leg of 1,2-2, which was
previously attached to the track through a center whose
stereochemistry was (S), has become the rear leg of 2,3-2
and the (same) center it is attached to has become (R) by
virtue of the change in the macrocycle position on the
track. As the enzyme selectively hydrolyzes the rear (R)-
attached foot each time, the enzyme hydrolyzes 2,3-2 to
form 3-1, after which the walker has taken two steps di-
rectionally along the three-foothold track (Scheme 1a, top
sequence). Since the directional walking results from the
enzyme’s selective hydrolysis of whichever foot is to the
rear, the mechanism corresponds to an information
ratchet type of Brownian ratchet mechanism.10
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Motor-proteins take occasional double steps and the
flexibility of the polyether track should make over-
stepping a significant process for synthetic walker 3 too.
Hydrolysis of the rear leg of 1,3-2—still reacting in prefer-
ence to the front leg as the rear leg is attached through an
(R)-stereocenter—allows the walker to step directionally
to the terminal position of the track through a ‘double-
step’ mechanism (Scheme 1, bottom sequence).
Scheme 1a shows the walking process. The walker begins
as hydroxy-acid 1-1, which cyclizes with the track to form
macrocycle 1,2-2 (Scheme 1a, top sequence, I) The ester
linkages that fix the walker to the track in 1,2-2 are stereo-
chemically distinct. Lipase AS—identified as a suitable
enzyme in screening studies (see Supporting Infor-
Scheme 1. Directional transport of a small-molecule biped with chemically identical feet.
a) Interconversion of walker-track conjugates under operation cycles consisting of I: Macrocyclization (2,4,6-TCBC, DMAP, Et3N,
CHCl3, 0.05 mM, rt, 20 h) and II: Enzyme hydrolysis (lipase AS (3.0 eq. w/w), H2O, 18 mM, 40 °C, 40-64 h). b) Table and c) graph
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showing the population of walker-track positional isomers 1-1, 2-1 and 3-1 after each operation cycle (see Supporting Information,
margin of error ±3 %). TCBC: trichlorobenzoyl chloride; DMAP: 4-(dimethylamino)pyridine; lipase AS: lipase AS ‘Amano’ (lipase
from Aspergillus niger).
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Characterization of Different Positions of the Walker
on the Track
sponding signal is a triplet (Figures 2d–f). The similarity
of the H NMR spectra of 1,2-2 (Figure 2b) and 2,3-2 (Fig-
ure 2d) suggests these macrocycles adopt very similar
conformations.
1
Acid 1-1 and macrocycles 1,2-2 and 2,3-2 were prepared
unambiguously through synthesis, acids 2-1 and 3-1 were
isolated from enzymatic hydrolysis of 1,2-2 and 2,3-2, re-
spectively, and 1,3-2 was obtained by preparative thin-
layer chromatography of a mixture of 1,3-2 and 1,2-2 fol-
lowing macrocyclization of 1-1 (see Supporting Infor-
mation for synthetic procedures and characterization
data). Each compound could be distinguished from the
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Ring-Opening and Ring-Closing Experiments
The individual parts of the walking mechanism were ini-
tially studied by subjecting macrocycles 1,2-2 and 2,3-2 to
enzymatic-hydrolysis–macrocyclization operation condi-
tions (Scheme 1a, see Supporting Information).
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others by H NMR spectroscopy (Figure 2). The chemical
Walker-track conjugate 1,2-2 was treated with lipase AS
(Scheme 1a, process II: lipase AS, 3.0 equiv. w/w, H2O, 18
mM, 40 °C, 40 h). After filtration and evaporation of the
shifts of the methine protons of the glycerol subunits, Ha,
Hb and Hc, are diagnostic of the position of the walker on
the track. Esterification of the footholds leads to down-
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solvent, H NMR spectroscopy indicated that the enzyme
field shifts in the H NMR spectrum from 3.9–4.0 ppm to
had hydrolyzed 1,2-2 with excellent regioselectivity, giving
1-1:2-1 in a 3:97 ratio (Figure S5, Supporting Information)
accompanied by 4 % of diacid 3, the product of fully de-
taching the walker from the track. The formation of rela-
tively little 3 shows that lipase AS distinguishes effectively
between macrocycle 1,2-2—its preferred substrate—and
the open-chain form, 2-1; this is a key result for achieving
significant processivity during the walking sequence.
5.2–5.3 ppm. In the macrocyclic conjugates, the methine
signal at the (R)-stereocenter (Ha in Figures 2b and 2f and
Hb in Figure 2d) is 0.5–1.5 ppm further downfield than
that the equivalent (S)-stereocenter. Additional clarity in
determining the walker position on the track was provid-
ed by deuterium labeling of the methylene group adjacent
to Hc. When the walker is at positions 1- or 2-, a pentet is
observed at 5.2–5.3 ppm (Figures 2a–d and 2f) whereas
when the walker reaches the final foothold the corre-
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Figure 2. Partial 1H NMR spectra (600 MHz, CDCl3, 298K) of walker-track conjugates. a) 1-1, b) 1,2-2, c) 2-1, d) 2,3-2, e) 3-1 and f)
1,3-2. Dashed lines connect the methine protons (Ha, Hb and Hc, blue) of the track footholds, the methine protons (Hd and He)
and the methylene protons (Hf and Hg) of the walker (red), and are diagnostic of the walker’s position on the track. Proton as-
signments correspond to the lettering in Scheme 1a. Signals due to residual solvents are shown in light grey.
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Macrocyclization of the 1-1:2-1 (3:97) product mixture was
carried out using a Yamaguchi protocol11 (Scheme 1a, pro-
cess I: 2,4,6-TCBC, DMAP, CHCl3, 0.05 mM, rt, 20 h),
leading to a 48:51:1 ratio of 1,2-2:2,3-2:1,3-2. Following the
essentially non-directional macrocyclization of 2-1 (to
form 1,2-2 and 2,3-2) 51 % of walkers had taken one step
directionally along the track by a passing-leg gait after
one hydrolysis-macrocyclization cycle.
taken one step (2-1), while 10 % remained at the starting
position (1-1) (cycle 4, Scheme 1b and 1c). The processivity
remained good over four cycles of operation, with 1-4 % of
diacid 3 lost during each enzyme hydrolysis stage. This
suggests that the small-molecule walker should be able to
take an average of at least 17 steps before fully dissociating
when directionally walking along a longer track (see Sup-
porting Information).
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Walker-track conjugate 2,3-2 was similarly subjected to
lipase AS (3.0 equiv. w/w, in H2O, 12 mM, 40 °C, 40 h)
leading to 93 % conversion to 2-1 and 3-1. Hydrolysis oc-
curred preferentially at the ester linkage adjacent to the
(R)-stereocenter, affording 3-1 with 94 % selectivity (Fig-
ure S6, Supporting Information). Diacid 3 again constitut-
ed ≤4% of the product mixture. Macrocyclization of the
product mixture led to a 2:53:45 ratio of 1,2-2:2,3-2:1,3-2.
The formation of 1,3-2 as a major component in this reac-
tion suggests that the double-step mechanism could play
a significant role if the walker was used to traverse an
extended form of the track with additional footholds.
CONCLUSIONS
The chemically identical feet of a small-molecule walker
can be discriminated on an isotactic track by exploiting
the stereochemical differences in foot environment in-
duced by macrocyclization of the walker with the track.
Lipase AS hydrolyzes the rear foot ester linkages of a
(R,R)-(+)-hydrobenzoin-based walker with up to 97 %
regioselectivity. The process can be combined with (unse-
lective) macrocyclization reactions to produce directional
migration of the walker along the track. After four macro-
cyclization-hydrolysis operations on a three-foothold
track, 90 % of walkers had moved away from the starting
position, with 68 % two steps further down the track. In
order to favor passing-leg over double-step mechanisms it
may be necessary to employ more rigid strand designs for
extended tracks.
Four Walking Cycles Starting from Walker-Track
Conjugate 1-1.
With the outcomes of the ring-opening and ring-closing
reactions established for each intermediate, the small-
molecule walker 1-1 was operated through four cycles of
macrocyclization/enzymatic hydrolysis (Scheme 1). The
changing distribution of the complex mixture was con-
sistent with modeling the transformations as a series of
Markov chains10d,12 using the ring-opening/closing exper-
imental data (see Supporting Information). Macrocycliza-
tion of walker-track conjugate 1-1 (Scheme 1, I) led to a
58:42 mixture of macrocycles 1,2-2 and 1,3-2 (Figure S8b
and Table S5, Supporting Information). This mixture was
treated with the enzyme (Scheme 1, II) generating a
15:56:29 mixture of 1-1:2-1:3-1 (cycle 1, Schemes 1b and 1c
and Figure S9, Supporting Information). Lipase AS hydro-
lyzes the 25-membered macrocycle 1,3-2, with 70 % selec-
tivity for the (R)-stereocenter, i.e. the rear leg of the walk-
er (Figure S9, Supporting Information). As a result 29 %
of walkers reach the terminal foothold after only one
operation cycle by double-stepping. The majority of walk-
ers (56 %) take one step directionally along the track,
forming 2-1 by a passing-leg gait (cycle 1, Scheme 1b and
1c).
All biomolecular walkers are also enzymes (their direc-
tional movement is powered by their catalysis of ATP
hydrolysis).1 The use of an enzyme to control the direc-
tionality of an artificial small-molecule walker marries a
biological machine with a synthetic one in a new form of
hybrid bio-synthetic walker mechanism.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, spectroscopic data and operation
details of the molecular walkers. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*david.leigh@manchester.ac.uk
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was funded by the Engineering and Physical
Sciences Research Council (EP/H021620/1&2) and the ERC
(Advanced Grant no. 339019). We thank the EPSRC National
Mass Spectrometry Centre (Swansea, U.K.) for high-
resolution mass spectrometry and the University of Man-
After repeating the macrocyclization-hydrolysis opera-
tions a further three times (cycles 2-4, Scheme 1b and 1c),
the distribution approaches a steady-state in which 68 %
of the walkers have taken two steps directionally along
the track (forming 3-1). Of the other walkers, 22 % had
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García, L.; Kantorovitch, L.; Amabilino, D. B.; Raval, R. Angew.
chester for a Dean’s Award (to CM). DAL is a Royal Society
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Chem. Int. Ed. 2015, 54, 7101–7105.
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