assembling oppositely charged lock and key responsive … · moresponsive and soft colloids as d...

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1Division of Physical Chemistry, Department of Chemistry, Lund University, Lund,Sweden. 2Division of Theoretical Chemistry, Department of Chemistry, Lund Uni-versity, Lund, Sweden.*Corresponding author. Email: [email protected]

Mihut et al., Sci. Adv. 2017;3 : e1700321 15 September 2017

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Assembling oppositely charged lock and keyresponsive colloids: A mesoscale analogof adaptive chemistryAdriana M. Mihut,1 Björn Stenqvist,1,2 Mikael Lund,2 Peter Schurtenberger,1 Jérôme J. Crassous1*

We have seen a considerable effort in colloid sciences to copy Nature’s successful strategies to fabricate complexfunctional structures through self-assembly. This includes attempts to design colloidal building blocks and theirintermolecular interactions, such as creating the colloidal analogs of directionalmolecular interactions, molecular rec-ognition, host-guest systems, and specific binding. We show that we can use oppositely charged thermoresponsiveparticles with complementary shapes, such as spherical and bowl-shaped particles, to implement an externally con-trollable lock-and-key self-assembly mechanism. The use of tunable electrostatic interactions combined with thetemperature-dependent size and shape and van derWaals interactions of these building blocks provides an exquis-ite control over the selectivity and specificity of the interactions and self-assembly process. The dynamic nature ofthe mechanism allows for reversibly cycling through various structures that range from weakly structured denseliquids to well-defined molecule-shaped clusters with different configurations through variations in temperatureand ionic strength. We link this complex and dynamic self-assembly behavior to the relevantmolecular interactions,such as screened Coulomb and van der Waals forces and the geometrical complementarity of the two buildingblocks, and discuss our findings in the context of the concepts of adaptive chemistry recently introduced to molec-ular systems.

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INTRODUCTIONThe use of colloids as model atoms or molecules in attempts to inves-tigate various aspects of phase transitions or to fabricate photonicmaterials has led to enormous progress in the development of modelparticleswith increasing complexity and their assembly into fascinatingnovel crystalline structures (1–8). Given the limitations in availableself-assembled structures for spherical particles with centrosymmetricinteraction potentials, the focus has gradually shifted to particles withdirectional interactions, such as anisotropic colloids, patchy particles,or well-defined colloidal clusters (6–10), where individual particlescan additionally be functionalized with DNA strands to also achievea notion of valency in colloidal self-assembly (5, 11).

Colloid scientists have made a considerable effort to copy variousstrategies that Nature uses successfully to create complex structuresthrough self-assembly. As an example, in their pioneering work,Sacanna et al. (14) have adapted the concept of a lock-and-keymechanism originally proposed by Fisher (12, 13) for colloidal mix-tures of complementary shapes, driven by the use of an additionaldepletion interaction. Although most studies focus on the use ofdepletion interactions to direct this specific self-assembly (14–17),alternative approaches have been considered (18–21).

Despite all this effort, in colloid sciences, we are still far from theprogress achieved in molecular systems, where concepts, such as su-pramolecular chemistry, constitutional dynamic chemistry (CDC), andadaptive chemistry pioneered by theNobel Prizewinner Jean-Marie Lehn,have led to enormous progress in creating novel materials. Althoughclassical self-assembly by design strives to achieve full control over theoutput molecular or supramolecular entity by explicit programmingof the building blocks and their interactions, adaptive chemistry pro-

vides self-organization with variable selection through the utilizationof reversible bonds that allow for a continuous change in constitutionby a dynamic reorganization and exchange of building blocks (22).

Here, we show thatwe can use oppositely charged thermoresponsivecore-shell particles with complementary shapes to achieve preciselytunable selectivity and specificity in colloidal self-assembly. We dem-onstrate that this offers the design of externally tunable and triggerablelock-and-key mechanisms and thus the colloidal analog of supra-molecular chemistry. Because of the considerable changes in overallsize, local curvature, van derWaals attraction, and surface charge den-sity that can be reached in thermoresponsive core-shell particles withcomplementary shapes, such as spherical and bowl-shaped particles,we can also attempt to implement the concept of adaptive chemistryorCDC in colloidal suspensions.Here,we successfully use variations intemperature and/or ionic strength to reversibly drive a binary mixtureof oppositely charged thermoresponsive particles with complementaryshapes (spherical and bowl-shaped) from unstructured dense liquidsintowell-definedmolecule-shaped clusterswith variable configurations.

RESULTSResponsive lock and key particlesOur approach aims to adjust the interactions and size of responsiveand soft host and guest particles to control their specific supracolloidalself-assembly with temperature. Here, we use oppositely charged ther-moresponsive and soft colloids as dynamic building blocks. The lockand key roles are played by a bowl-shaped composite microgel and aspherical microgel, respectively. Composite polymer microgels are theideal candidates for implementing this directed self-assembly throughexternally controllable interactions. As a result of the thermosensitiveshell, which undergoes a temperature-induced volume phase transition(VPT) (23), their overall size and the interaction potential can beprecisely controlled via temperature (24). We follow a processingroute described in our former study to create a bowl-shaped composite

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microgel consisting of a polystyrene (PS) core and a fluorescent poly(N-isopropylmethacrylamide) (PNIPMAM) shell (25). This system canthen be used as a tunable lock particle in the presence of an oppositelycharged poly(N-isopropylacrylamide) (PNIPAM) microgel serving asthe key particle.

A confocal laser scanningmicroscopy (CLSM) image of the bowl-shaped core-shell composite microgels is shown in Fig. 1A. Thespherical particle synthesis, which is described in Materials andMethods and our previous study (26), leads to monodisperse parti-cles with a PS core that has a radius of 267 ± 20 nm from a statisticalanalysis of transmission electron microscopy images. CLSM at 20°Cevidences the fluorescent shell covalently labeled with rhodamine. Atthis temperature, the shell thickness is comparable to the core radiusas indicated by the hydrodynamic radius of the particle, RH = 479 nm,measured by dynamic light scattering (DLS). These particles werefurther postprocessed into bowl-shaped particles following the ap-proach of Im et al. (27), as described in Materials and Methods andour recent work (25). In short, the core-shell particles were swollenwith styrene, vitrified in liquid nitrogen, and then equilibrated below0°C to let the styrene evaporate. A cavity is created at the surface of theparticle by styrene evaporation flux. The resulting particles, used asthermoresponsive locks, are monodisperse in size and shape (seeFig. 1A). The lock particles have an overall radius RL = 497 ± 16 nmmeasured byCLSMand a slight bowl-shaped anisotropy characterizedby an apparent aspect ratio of approximately 1.4 (25). The selected keyparticles shown in Fig. 1B consist of fluorescently labeled (fluorescein)


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cross-linked (5 mole percent) PNIPAM microgels with a radius RK =443 nmdetermined byDLS at 20°C.We refer to our former study (28)and Materials and Methods for further details concerning their syn-thesis and characterization.

The swelling behavior of the lock and key particles was charac-terized using DLS. Here, we follow the evolution of the hydrodynamicradius as a function of temperature. PNIPAMand PNIPMAMmicrogelsrespond to temperature with a transition from a swollen to a col-lapsed configuration with increasing temperature at the VPT tem-perature, TVPT. DLS measurements shown in Fig. 1C confirm thisfeature for the different particles, with a transition at 32°C for the cat-ionic PNIPAM microgels and at about 42°C for the anionic sphericaland bowl-shaped PS/PNIPMAM composite microgels. Selecting tworesponsive polymers with two different TVPT has the advantage of afine-tuning of their sizes and interactions, which can be described inthree regions, as illustrated in the same figure. BelowTVPT,key in region 1,both components are swollen. BetweenTVPT,key andTVPT,lock in region 2,only the key particles significantly reduce their size, whereas the lockparticles maintain a swollen state. For T > TVPT,lock in region 3, bothcomponents are collapsed.

The lock and key particles are oppositely charged, as confirmed byelectrophoretic mobility measurements shown in Fig. 1D. The anioniccharacter of the bowl-shaped particles comes from the potassium per-oxydisulfate (KPS) initiator and some remaining SDS surfactant,whereas the pure microgel particles are cationic because of the am-idine end groups from the 2,2′-azobis(2-methylpropionamidine)dihydrochloride (V50) initiator. The electrophoretic mobility m is sen-sitive to temperature and most particularly to the conformation of themicrogel. It results in an increase in the effective charge of the particlesat higher temperatures with a transition at TVPT, as documented in theliterature (29). For the composite microgels, a similar temperaturedependence of the electrophoretic mobility was observed for sphericaland bowl-shaped particles. In addition, postprocessing sphericalcomposite microgel into bowl-shaped particles did not strongly affectthe swelling behavior, as expected from the slight anisotropy of thebowl-shaped particles and the fact that the postprocessing is almostan isochore transformation (25).

Lock-and-key interaction potentialThe extension of the lock-and-key principle to colloids and morecomplex interaction potentials is based on the idea that interactionsare maximized for particles with matching geometries. Combiningcomplementary shape with additional and tunable interparticle in-teractions then results in an effective pair potential between the lockand key particles that is strongly dependent on the relative orientationand particle dimensions. Moreover, it provides us with an implemen-tation of interaction specificity and selectivity that can be variedthrough external parameters, such as temperature and ionic strength.For a more generic description of the interactions at play, the lockparticle is described by an indented sphere defined by the differencebetween two equal spheres, where the maximum contact area is pR2

L,as shown in Fig. 2A. The electrostatic interactions are treated byconsidering that the charges are randomly distributed at the surfaceof the two components and that opposite charges are interacting viaa screened Coulomb potential

VSCðrÞ ¼ � e2

4pD0Dr

e�kr

rð1Þ

B

A

−6

−4

−2

0

2

20 30 40 50 60T [oC]

μ[µ

mcm

V−1

s−1]

1 2 3

D

C

200

300

400

RH

[ nm

]

“Lock”

“Key”

Fig. 1. Responsive lock-and-key microgel particle characterization. (A) CLSMmicrographs of bowl-shaped composite microgels fluorescently labeled in red(rhodamine dye) used as a lock particle. (B) Key particles consisting of cross-linkedPNIPAM microgel particles labeled in green (fluorescein), as imaged by CLSM.Scale bars, 1 mm. (C and D) Hydrodynamic radius and electrophoretic mobilitymeasured as a function of temperature: bowl-shaped lock composite microgel(solid circles) and spherical key microgel particle (solid squares). The measure-ments cross three regions delimited by the VPT temperature of the lock-and-key particles, TVPT,L and TVPT,K. In region 1 (T < TVPT,K), both particles are swollen.In region 2 (TVPT,K ≤ T ≤ TVPT,L), lock particles are swollen and key particles arecollapsed. In region 3 (TVPT,L < T ), both particles are collapsed.

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where D0 is the dielectric permittivity of vacuum, Dr is the relative di-electric constant, e is the elementary charge, and r is the distance be-tween the surface charges. k is the inverse Debye length defined as

k ¼ e2NAcsaltD0DrkBT

� �12

ð2Þ

where csalt is the molar concentration of monovalent salt.Calculations were further performed to determine the minimum

electrostatic energy, Vel, at contact in either the lock-and-key (LK)configuration (Vel,LK) or the opposite (LK) configuration (Vel;LK)),as schematically depicted in the insets of Fig. 2 (B and C). These two


quantities were first evaluated at 25°C and different ionic strengths as afunction of the lock-and-key particle size ratio. The size of the lock par-ticle was fixed to RL = 500 nm, and the total charges were consideredto be constant and equal to ZL = −1000e and ZK = +100e. The ionicstrength was varied from a fully deionized condition (csalt = 10−5 M,kRL ≈ 5) to the highly screened regime (csalt = 10−2 M, kRL ≈ 164),and the size ratio was varied from 0.04 to 2. As expected from screenedCoulomb interactions, the minimum interaction energy strongly de-pends on the ionic strength. In the optimal configuration correspondingto RK/RL = 1, Vel,LK varies from Vel,LK ≈ 4.5 kBT under deionizedconditions to Vel,LK ≈ 0.18 kBT at csalt = 2.1 × 10−3 M. In comparison,Vel;LK is more sensitive to the variation of the ionic strength and de-creases fromVel;LK≈ 1 kBT toVel;LK≈ 3 × 10−3 kBT.Worth noting is thenonmonotonic dependence of Vel,LK, with an inflexion point aroundRK/RL = 1 at low ionic strengths, which develops to a pronouncedmaximum as csalt increases. This is in contrast to the behavior foundfor Vel;LK , which decreases monotonically with increasing RK/RL.These calculations demonstrate that the specificity of the assemblythat we define through the difference between Vel;LK and Vel,LK ismaximal for two matching geometries and is promoted at a lowerionic strength, as shown in Fig. 2D.

The total effective charge, Z, and the surface charge density, s,were evaluated at different temperatures from the measured elec-trophoretic mobility, m, and hydrodynamic radius, RH, assuming Z =6phRHm and s =Z=ð4pR2

HÞ. The total charges of the lock and key, ZLand ZK, vary with temperature from +98e and −1041e at 20°C to+182e and −1300e at 40°C. This corresponds to a continuous increaseof −sK/sL from about 1/9.25 to 1/2.90 in this temperature range,followed by a decrease to 1/4.26 after the VPT of the bowl-shapedparticles at 50°C. These experimental values were further used asinput parameters in the model described above to estimate Vel,LK andVel;LK at different temperatures, as summarized in Fig. 3A. The dif-ference of the electrostatic energies, ðVel;LK � Vel;LKÞ, was found tovary from 5 to 11 kBT between 20° and 40°C to finally reach a valueof≈20 kBT at 50°C. The specificity of the assembly is strongly relatedto the surface charge density of the two components considering thatVel is proportional to sLsK.

Van derWaals interactions were estimated for three limiting casescenarios (30). First, in the LK configuration, the interactions sim-plify to the case of two spheres with their respective Hamaker con-stants, AK and AL, whose surfaces are separated by a distance h

VvdW;LKðhÞ ¼ALAKRLRK

6hðALRL þ AKRKÞ ð3Þ

In the second case, when RK << RL in an LK configuration, theinteractions are comparable to a sphere interacting with an infiniteplane such that

VvdW;LKðhÞ ¼ ðAL þ AKÞRK

12h; RK << RL ð4Þ

Finally, when RL ≈ RK in the LK configuration, the interactionscan be approximated by two parallel planes having a surfaceS ¼ pR2

K,which results in

VvdW;LKðhÞ ¼ ðAL þ AKÞS24ph2

¼ ðAL þ AKÞR2K

24h2; RL ≈ RK ð5Þ

“LK”

1.0.10−5 M2.1.10−5 M4.6.10−5 M1.0.10−4 M2.1.10−4 M4.6.10−4 M1.0.10−3 M2.1.10−3 M4.6.10−3 M1.0.10−2 M

“LK”

RL

RK

- - --

--

---

-

- - --

--

---

--

+++

++

++ +

++

++

++

ZL ZK

Ionic strength

10−3

10−2

10−1

100

0 0.5 1.0 1.5 2.0

10−3

10−2

10−1

100

101

10−3

10−2

100

101

A−V

el,L

K[k

BT]

−V

10−1

el,L

K[k

BT]

+V

el,L

K−V

el,L

K[k

BT]

B

C

D

RK/RL

Fig. 2. Calculations of the electrostatically driven self-assembly of oppositelycharged lock and key particles. (A) Schematic representation of the oppositelycharged lock and key particles used for the modeling of electrostatic interactions.(B) Minimum electrostatic energy in the lock-and-key (LK) configuration as afunction of the size ratio, RK/RL, calculated for different ionic strengths using RL =500 nm, ZL = −1000e, and ZK = +100e. (C) Same calculations as in (B) but in the LKconfiguration. (D) Energy difference between the LK and LK configurations at dif-ferent ionic strengths (see text for more details).

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We ignored the case where RK > RL, which cannot be so easilycaptured and does not correspond to our simplified model wherekey particles are always considered smaller than the lock particles.In addition, although the above approximations are valid in most ofthe configurations, they do not hold when the key particle is in closevicinity of the lock cavity rim.

The microgel particles are highly swollen with water, and theirHamaker constant therefore strongly depends on their degree ofswelling. We considered that the polymer volume fraction of the


microgel fp(T) scales with the overall size of the particles, givenby the evolution of their hydrodynamic radii with temperature

fpðTÞ ¼R3H;coll

RHðTÞ3⋅fp;0 ð6Þ

where RH,coll refers to the hydrodynamic radius of the fully col-lapsed particles, and fp,0 refers to the polymer volume fraction inthe collapse state. For a core-shell particle with a core radius Rc, asimilar calculation can be derived

fpðTÞ ¼R3H;coll � R3

c

R3H;coll � R3

c⋅fp;0 ð7Þ

Following the approach proposed by Rasmusson et al. (31), wecan first estimate the Hamaker constant of the swollen microgel fora given temperature T, Am(T), as

AmðTÞ ¼ fpðTÞA0:5p þ ð1� fpðTÞÞA0:5

w

h i2ð8Þ

where Ap and Aw are the Hamaker constants of the microgel (Ap =6.20 × 10−20 J) and water (Aw = 3.7 × 10−20 J), respectively (31). Aneffective Hamaker constant, Aeff(T), can then be estimated for themicrogel

Aeff ðTÞ ¼ ðAmðTÞ0:5 � A0:5w Þ2 ¼ ðA0:5

pol � A0:5w Þ2fpðTÞ2 ð9Þ

Wecan now apply the different calculations to the lock and key par-ticles. Ap was assumed to be the same for PNIPAM and PNIPMAM,and fp was determined for the lock particles from the measurements ofthe spherical core-shell microgels. In addition, because the shell thick-ness is larger than 100 nm, we have neglected the contribution of thePS core. The different values derived from these calculations are sum-marized in Fig. 3B.VvdW was found to vary from 8.7 × 10−2 to 4.2 kBTat 20°C and from1.2 to 25 kBT at 50°C. Van derWaals interactions aretherefore expected to be non-negligible even in the swollen state.However, our model assumes a constant polymer density across theradial density profile at each temperature, which is not the case whenthe particles are swollen (28, 32). As a consequence, the van derWaalscontribution is expected to be negligible at low temperatures becauseof the fuzzy outer structure of the swollenmicrogels and to only becomeeffective when at least one of the components is in its collapsed state. Inthis case, similarly to electrostatic interactions, these simple calculationsdemonstrate the specificity of the lock-and-key assembly.

Besides electrostatic and van der Waals interactions, there is anentropy loss in the LK configuration. An analytical expression wasderived to account for the entropic contribution expressed by thefree energy DG of hard lock and key particles with different geomet-rical parameters, as detailed in the Supplementary Materials. For thelock geometry previously discussed, the expression simplifies to

DGðdÞ¼�kBT ln

ðRK � dÞðRK � 2RL þ dÞ4dRL

� �; RK ≤ d < dlim

�kBT ln12þ 12cos

p3þ cos�1 R2

K � R2L � d2

2dRL

� �� ; dlim ≤ d ≤ RL þ RK

0 ; RL þ RK < d

8>>>><>>>>:

ð10Þ

−Vvd

W,L

K/kBT

,−V

vdW

,LK/k

BT−V

el,L

K/kBT

,−V

el,L

K/kBT

A

B

T [oC]

C

1

2

5

10

20

50

0.1

1

10

σΚσL

2

4

6

8

10

20 30 40 50

dC = 1 nmdC = 5 nmdC = 10

nm

dC = 20

nm

ΔG/k

BT=

−ΔS

/kB

Fig. 3. Minimum electrostatic energy of the specific and unspecific self-assembly between lock and key particles. (A) Minimum electrostatic energydetermined at csalt = 10−5 M from the calculations in the LK (empty circles) and LK(solid circles) assemblies schematically depicted by the insets. (B) Van der Waals in-teraction contribution determined at a separation distance of 10 nm in three limitingcases illustrated by the corresponding schematic representations: RL ≈ RK in LKconfiguration reducing to a plane-plane approximation (solid circles); RK << RL inLK configuration, where the interaction simplifies to a sphere-plane approximation(solid squares); and lock and key particles in LK configuration corresponding to asphere-sphere approximation (empty circles). (C) Entropy contribution to the freeenergy at different distances from the ideal contact (see text and the SupplementaryMaterials). The schematics represent the relative size of the lock and key particles atdifferent temperatures pointed by the arrows.

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where d is the distance between the centers of the lock and key par-ticles and dlim = ðR2

K � RKRL þ R2LÞ

12. The minimum distance at con-

tact is RK when RK ≤ RL and ðð4R2K � 3R2

LÞ12 þ RLÞ=2 when RK > RL.

Detailed calculations ofDG(d) for different RK/RL ratios are providedin fig. S2. The analytical expression was confirmed by Monte Carlosimulation for different RK/RL ratios (see fig. S2).

As the entropy diverges at contact, we have evaluated the freeenergy at a different distance to the “ideal” lock-and-key configuration,dc = d − RK, varying from 1 to 20 nm, considering the overall size ofthe two particles measured from 20° to 50°C. These results, summa-rized in Fig. 3C, show that for this simplified geometrical model, DGvaries between≈10 and 4 kBT over the temperature range. The max-imum value was found at 20°C where RK/RL is slightly below unity,whereas the minimum was at 35°C when RK/RL is the lowest. In ad-dition, DG quickly drops by a few kBT with increasing dc. Even so, theentropy contribution is expected to be lower in our experiments par-ticularly at low temperatures, given the soft and deformable nature ofthe swollenmicrogel particles. In summary, the proposedmodel dem-onstrates that the binding energy could overcome the entropic penaltyto bind the key particles in an LK configuration particularly if the sur-face charges of the two components are properly adjusted.

Lock-and-key responsive assemblyHaving established a sound description of the orientation-dependentinteraction potential for our lock-and-key mechanism, we now turnto the resulting self-assembly behavior in mixtures of these particles.We first investigate a mixture of lock particles [1 weight % (wt %)]and key particles (0.27 wt %) with increasing ionic strength set by theaddition of variable amounts of potassium chloride at 20°C, asshown in Fig. 4. The number density of the microgel particles wasestimated from their size in the collapsed state, assuming a polymervolume fraction of 0.8 and using the density of PNIPAM, rPNIPAM =1.1495 g·cm−3 (28). For the core-shell particles, we used the radiusand density of the PS core (rPS = 1.054 g·cm−3) and the mass ratiobetween the core and shell from the synthesis conditions (≈0.5) tocalculate their number density. This results in a lock-to-key numberratio NL/NK ≈ 1.

Figure 4 confirms the electrostatic nature of the self-assembly inthese mixtures. At low ionic strength (csalt = 10−5 M), the particlesassociate into dense aggregates where most of the locks were occupied


by key particles (see Fig. 4A). Increasing the salt concentration to csalt =10−4 M results in less compact aggregates coexisting with smaller as-semblies (see Fig. 4B). Finally, at csalt = 2.5 × 10−3 M, only individualparticles were observed (see Fig. 4C). At the highest ionic strength, theweakly charged PNIPAM microgels were unstable above 32°C andbuilt up a loose network, whereas the lock particles were still diffusingfreely. However, at 48°C, the lock particles adsorbed on the PNIPAMmicrogel driven by the increase in the van der Waals interactions (seeFig. 4D).

Next, we investigate the influence of NL/NK at constant numberdensity of lock particles (NL/V ≈ 6.8 × 10−2 mm−3) and low ionicstrength (csalt = 10−5M), as shown in Fig. 5. As discussed in the formersection, forNL/NK≈ 1, lock and key particles built up dense aggregatesby electrostatic interactions, combining specific LK and unspecificLK assemblies (Fig. 5A). At this number ratio, the number of lockparticles is insufficient to stabilize the key particles, thus resulting inthe formation of large and compact aggregates. Similar observationswere made at NL/NK ≈ 2 (Fig. 5B), whereas for NL/NK ≈ 6, particlesrearranged into looser aggregates coexisting with defined tetrahedralassemblies (referred to as tetramers), consisting of a key particle sta-bilized by four lock particles. The high specificity of the assembly wasasserted by counting the fraction of key particles presenting at leastone LK association, defined as f(NLK), which increased from ≈67 to≈90%with increasingNL/NK values (see fig. S3 and the SupplementaryMaterials for details). It is worth pointing out the dynamic character oflock-and-key assemblies because some lock particles are released fromthe LK configuration from time to time at 20°C. This is in line with ourestimate of a weak interaction potential of about 5 kBT. The interactionbetween lock and key particles at this temperature is thus sometimesinsufficient to permanently bind all particles in an LK configuration.

The tetrahedral “methane”-like assembly observed at 20°C has tobe seen in conjunction with the geometry of the two particles. Whenboth particles are considered as oppositely charged spheres with radiigiven by their hydrodynamic radii, one would expect a key particle tobe stabilized (or decorated) by approximately4KðRL þ RKÞ2=R2

L ≈ 13particles adsorbed to its surface at 20°C, where the prefactor K≈ 0.9is the maximum two-dimensional (2D) sphere packing. However,only amaximumof four particles were observed to stabilize the key par-ticles present in an excess of lock particles. In addition, the average dis-tance between the two components, dLK, was much smaller than the

csalt−510 M −410 M 2.5 × 10−3 M

Slow quenchingo20 C o48 C

A B C D

Fig. 4. Influence of the ionic strength on the lock-and-key self-assembly. (A to C) 2D CLSM micrographs of the lock and key particles (cL = 1 wt %, NL/NK ≈ 1)recorded at 20°C at various ionic strengths [(A) csalt = 10−5 M, (B) csalt = 10−4 M, and (C) csalt = 2.5 × 10−3 M]. (D) By slowly rising the temperature from 20° to 48°C at anionic strength of 2.5 × 10−3 M, the key microgel particles become unstable above their TVPT,key and form a network onto which the lock particles unspecifically adsorbfor T ≳ TVPT,lock. Scale bars, 2 mm.

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sum of the two hydrodynamic radii, with dLK≈ 0.58 mm≈ 0.63(RL +RK). This observation asserts that the particles are almost in contactwith the preferential LK configuration, thus explaining the reducednumber of particles in the colloidal molecule assembly.

The effect of temperature is then investigated for a constant num-ber ratio ofNL/NK≈ 6. Here, T is increased from 20° to 40°C and thenfrom 40° to 48°C, as shown in Fig. 6A. This initially results in a signif-icant shrinkage of the PNIPAM key particles, which are in their fullycollapsed state at T = 40°C, whereas the PNIPMAM functionalizedlock particles are still highly swollen. As a consequence of the largersize ratio, key particles mostly assemble with two lock particles into alinear “carbon dioxide”–like configuration, whichwe define as dimers,where dLK≈ 0.38 mm≈ 0.58(RL + RK). This assembly was observed inthe form of free dimers coexisting with trimers (association with three


lock particles) and larger aggregates. The hierarchical self-assembly ofthe clusters was attributed to the incomplete coverage of the key par-ticles by the lock particles. No dynamic release of particles was ob-served at this temperature, indicating that the interactions are muchstronger, in agreement with the temperature-induced increase in theestimated surface charge density of both components and the additionalcontribution from van der Waals interactions. Finally, increasing thetemperature to 48°C, where both components are in their collapsedconfigurations, leads to a compact assembly where a key particle isfully enclosed by two lock particles, resulting in dLK ≈ 0.24 mm ≈0.39(RL + RK). The small size of the assembly results in a significantlyfaster Brownian motion, which implies a large uncertainty in dLK atT = 48°C. The dumbbell shape at this temperature is reminiscent of a“dihydrogen”-like configuration, and we observe mainly individual

N /NL K≈1 ≈2 ≈6

A B C

Fig. 5. Influence of the number ratio NL/NK on the lock-and-key self-assembly. (A to C) 2D CLSM micrographs recorded at 20°C for dispersions prepared at lowionic strength (csalt ≈ 10−5 M), with cL = 1 wt % and different NL/NK values [(A) NL/NK ≈ 1, (B) NL/NK ≈ 2, and (C) NL/NK ≈ 6] showing the transition from dense aggregateto colloidal molecules.

0

20

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ield

[%]

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20

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2: Dimers3: Trimers4: Tetramers>4: Aggregates

o20 C

o40 C

o48 C

≈50% ≈50%

Tetramers

100%

Dimers Trimers

≈100%

Dimers

Τo20 C

o40 C

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A B

“CH ”4

“CO ”2

“H ”2

Fig. 6. Influence of the temperature on the lock-and-key self-assembly into colloidal molecules with adjustable valency. (A) 2D CLSM micrographs of a dispersion(NL/V ≈ 6.8 × 10−2 mm−3, NL/NK ≈ 6) and schematic representations illustrating the specific self-assembly in colloidal molecules with a valency of ≈4 at 20°C (methane,CH4; top, configuration). Increasing the temperature to 40°C, the key particles exhibit a collapsed state, and the valency of the assembly decreases to ≈2 (carbondioxide, CO2; middle, configuration). When both the lock and key particles are in their collapsed state at 48°C, key microgels are confined between two lock particles(dihydrogen, H2; bottom, configuration). (B) Yield in colloidal molecules relative to the number of key particles determined from various time series recorded atdifferent temperatures. The statistics are supported by typical configurations observed in dispersion together with their relative fractions. Top left: Methaneconfiguration with NLK = 4. Top right: Tetramer with an unspecific contact and NLK = 3. Middle left: Carbon dioxide configuration. Middle right: Trimer with an unspecificcontact and NLK = 2. Bottom: Dihydrogen configuration. Scale bars, 1 mm.

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assemblies coexisting with free lock particles and small aggregates.This temperature-dependent self-assembly thus leads to a reconfig-urable formation of colloidal molecules that is thermoreversible, asshown in movie S1.

The temperature dependence of the assembly specificity wasillustrated by the variation of f(NLK) from ≈90% at 20°C to ≈100%at T ≥ 40°C, in qualitative agreement with our model and the addi-tional contribution of the van der Waals interactions at high tem-peratures (see fig. S4 and the Supplementary Materials for moredetails). The yield of the colloidal molecule assembly was determinedby counting the number of key particles forming isolated colloidal mol-ecules in respect to those assembled into aggregates, defined as an as-sociation including either more than two key particles or more thanfive lock particles. Thiswas estimated from the number of key particlesin the two populations visible in different frames from the 2D micro-graph time series. By tracking the colloidalmolecules on themovie, weasserted the presence of free dimers, trimers, and tetramers. The sta-tistical analysis shown in Fig. 6B illustrates that the association of thetwo particles chiefly leads to tetramers with a yield of ≈28% at 20°C.The tetrahedral assembly is characterized by two main states. Theideal case, which we referred to as the methane configuration, wherekey particles present four LK contacts (NLK = 4), is roughly represent-ative of 50% of the population and was found to coexist with colloidalmolecules where at least one of the contacts is unspecific (NLK < 4).Figure 6B displays snapshots of the two characteristic assemblies.When the key particles are in their collapsed state at 40°C, mostly di-mers and trimers were observed with a respective yield of ≈18 and≈14%.When the dimers present the ideal carbon dioxide configuration(NLK = 2), the trimers feature an unspecific lock particle adsorption inall observations (see snapshot in Fig. 6B). Thus, these trimers representthe intermediate configuration of the transition from tetramers to di-mers occurring with temperature, as confirmed by the results at 48°C,where only dimers coexisting with smaller aggregates with a large yieldof ≈50% were observed. As a general comment, the particles were notindex-matched and were imaged about 10 mm away from the surface.Therefore, the estimates for the yield at different temperatures were in-fluenced by the sedimentation of larger aggregates.

h 7, 2021
DISCUSSIONWe have shown that thermoresponsive particles can be processed intocomplementary geometrical shapes that allow us to implement an ex-ternally controllable lock-and-key assembly mechanism. Although col-loidal lock and key particles have been described previously, they havemostly been based on “hard” building blocks. This is in contrast tobiological systems, which are usually much softer and have the abilityto adapt their configuration in response to their local environment, asdescribed by the induced-fit theory formulated by Koshland (33, 34).We foresee that these findings will initiate further studies on morecomplex colloidal lock-and-key mechanisms using similar soft and re-sponsive colloidal building blocks to study the influence of softness anddeformability of the two components and develop the colloidal analogsof the induced-fit theory.
Moreover, our study has demonstrated that responsive and oppositelycharged colloidal particles with complementary shapes are ideal buildingblocks to extend the classical lock-and-key interactions to ahighly tunableand dynamic self-assembly process similar to the concept of adaptivechemistry introduced formolecular systems.We canuse the combinationof electrostatic interactions between complementary shapes, guiding


and driving the lock-and-key self-assembly process and the increasingcontributions from van der Waals attraction at higher temperatures tocreate and lock particular configurations. This has allowed us to assem-ble well-defined colloidal clusters with reconfigurable configurations,mimicking the colloidal analogs of structures, such as methane, carbondioxide, and dihydrogen. The geometrical complementarity of the par-ticles thus provides us with an association mechanism that implementsboth selectivity and specificity, whereas the responsive nature of bothbuilding blocks results in an exquisite control of these processes.

Adaptive chemistry or CDC provides self-organization with vari-able selection through the utilization of reversible bonds that allow fora continuous change in constitution by a dynamic reorganization andexchange of building blocks (22). This study has demonstrated thatour thermoreversible building blocks allow us to develop colloidalanalogs of these systems. We have shown that we can use variationsin temperature and/or ionic strength to reversibly drive a binary mix-ture of oppositely charged thermoresponsive particles with comple-mentary shapes (spherical and bowl-shaped) from unstructured orweakly structured dense liquids into well-defined molecule-shapedclusters with variable configurations. It will be interesting to seewhether this approach can be extended to more complex mixturesof responsive particles with carefully designed physical properties(size, shape, charge state, and monomer composition, resulting in dif-ferent swelling curves as a function of temperature), guided by the the-oretical description of the interactions introduced in this study, andinvestigating the wide range of dynamic system states that we canachieve in this manner. The ability of the lock-and-key colloids toundergo continuous conformational changes and to behave as “shapeshifters” allows for adaptive self-organization that is explicitly relatedto the dynamic exchange and reorganization process into a variety ofcolloidal molecules, endowing for assemblies capable to adapt to localor external stimuli. We further envision that the association of softthermoresponsive and oppositely charged key particles with multiva-lent colloids presenting a defined number of locks per particles (16, 35)could provide the adequate limited valence and tunability necessary toconstruct and grow well-defined higher-order structures, includingnon–close-packed crystals.

MATERIALS AND METHODSSynthesisMaterialsN-isopropylmethacrylamide (Sigma-Aldrich),N-isopropylacrylamide(NIPAM; Sigma-Aldrich), and N,N′-methylenebisacrylamide (BIS;Fluka) monomers and V50 (Fluka), SDS (Fluka), and potassium per-oxydisulfate (KPS; Fluka) were used as received. Styrene monomer(BASF) was purified on an Al2O3 column before use. Water was puri-fied using reverse osmosis (Milli-RO; Millipore) and ion exchange(Milli-Q; Millipore).Synthesis of composite PS-PNIPMAM microgelThe core-shell microgel was synthesized and characterized as describedin our former contribution, J. J. Crassous et al. (25), as is their postpro-cessing into bowl-shaped particles. We refer to the J. J. Crassous et al.study (25), which presents the synthesis and characterization of theseparticles in more detail.Postprocessing of composite microgels intobowl-shaped particlesThe particles were first swollen with styrene and then quickly fro-zen into liquid nitrogen (−196°C). A void was created at the center

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of the particles as the styrene solidified from the surface to the centerof the PS core. In the next step, the frozen sample was slowlywarmed up to let the swollen agent evaporate. The evaporation pro-cess was carried out below 0°C under ambient pressure. Because ofthe presence of an evaporation flux of the styrene, a hole appears inthe shell of each hollow particle. We refer to the original work ofIm et al. (27) for a more detailed description of the shape transfor-mation mechanism.Synthesis of the key particlesIn a typical procedure, NIPAM (2 g) as monomers, BIS (0.136 g) asthe cross-linker, V50 (0.01 g in 10 ml of water) as the initiator, andfluorescein-5-isothiocyanate (2 mg dissolved in 87.8 ml of water) asthe dye were polymerized by precipitation polymerization. The reac-tion was run for 4 hours at 80°C. The reaction mixture was passedthrough glass wool to remove particulate matter and was furtherpurified by three centrifugation cycles at 10,000 rpm for 20min, withremoval of the supernatant and redispersion between each cycle.

Experimental methodsConfocal laser scanning microscopyThe confocal micrographs were monitored on a Leica SP5 CLSM op-erated in the inverted mode (D6000I) using a 100×/1.4–numericalaperture immersion objective. The samples were monitored in situat different temperatures, and an environmental system was used toensure temperature control with an accuracy of 0.2°C. The suspen-sions were kept between two cover glasses separated by a 120-mmspacer. A 488-nm Ar ion and a 543-nm He-Ne laser were used toexcite the red fluorescence of rhodamine B (543 nm) and the greenfluorescence of fluorescein (488 nm), respectively. The cover glassand coverslip were washed with 2 to 5% Decon 90 aqueous disper-sion, extensively rinsed with water and dried under nitrogen flowbefore use.Dynamic light scatteringDLS was carried out using a light scattering goniometer instrumentfrom LS Instruments equipped with a He-Ne laser (l = 632.8 nm).The temperature was controlled with an accuracy of 0.1°C. The sampleswere diluted to 0.01 wt %, preventing interaction effects and multiplescattering. The measurements were performed at scattering angles of45°, 60°, and 75° for temperatures varying between 20° and 55°C, withan equilibration time of 30 min before data collection. The hydro-dynamic radius was derived following a standard angular dependenceanalysis.Electrophoretic measurements and effectivecharge determinationThe effective charge, Zeff, was estimated from the particle electropho-retic mobility, m, determined with a Zetasizer Nano Z (Malvern) inpureMilli-Q. The dispersions were highly diluted (0.01 wt %) to avoidmultiple-scattering effects.Evaluation of the electrostatic energyThe lock particles were decorated with Ne = 10,000 point chargesrandomly distributed at their surface. The number of point chargeson the key particle was adjusted such that the point charge surfacedensity, defining themesh size, rL =Ne=ð4pR2

LÞ, was equal on the lockand key particles. The individual charges were then adjusted tomatch the total charge of the lock and key particles. The electrostaticenergy in the LK andLKwas then calculated as the sum of pair inter-actions of the ensemble of opposite charges. The reported results forany given size ratio and ionic strength were derived from the averageof five independently generated random charge distributions.


SUPPLEMENTARY MATERIALSSupplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/3/9/e1700321/DC1Determination of the entropic contribution for hard lock and key particlesEvaluation of the binding specificityfig. S1. Geometrical configuration of a particle in a lock-and-key assembly.fig. S2. Entropic contribution for hard lock and key particles.fig. S3. Binding specificity dependence of the mixing ratio between lock and key particles.fig. S4. Binding specificity dependence of the temperature at a constant mixing ratio.movie S1. Colloidal molecules with tunable valence via lock-and-key self-assembly.

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AcknowledgmentsFunding: We acknowledge financial support from the Knut and Alice Wallenberg Foundation(project grant KAW 2014.0052) and the European Research Council (ERC-339678-COMPASS).Author contributions: J.J.C. initiated the work. A.M.M. and J.J.C. conducted and designed theexperiments. B.S. and M.L. performed the calculations of the electrostatic interactions andsimulation. B.S. derived the model for the entropic contribution. J.J.C., A.M.M., and P.S.discussed the results and revised the manuscript at all stages. Competing interests: Theauthors declare that they have no competing interests. Data and materials availability: Alldata needed to evaluate the conclusions in the paper are present in the paper and/or theSupplementary Materials. Additional data related to this paper may be requested fromthe authors.

Submitted 31 January 2017Accepted 16 August 2017Published 15 September 201710.1126/sciadv.1700321

Citation: A. M. Mihut, B. Stenqvist, M. Lund, P. Schurtenberger, J. J. Crassous, Assemblingoppositely charged lock and key responsive colloids: A mesoscale analog of adaptivechemistry. Sci. Adv. 3, e1700321 (2017).

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adaptive chemistryAssembling oppositely charged lock and key responsive colloids: A mesoscale analog of

Adriana M. Mihut, Björn Stenqvist, Mikael Lund, Peter Schurtenberger and Jérôme J. Crassous

DOI: 10.1126/sciadv.1700321 (9), e1700321.3Sci Adv

ARTICLE TOOLS http://advances.sciencemag.org/content/3/9/e1700321

MATERIALSSUPPLEMENTARY http://advances.sciencemag.org/content/suppl/2017/09/11/3.9.e1700321.DC1

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