418 CHIMIA 2016, 70, No. 6 NCCR MoleCulaR SySteMS eNgiNeeRiNg

doi:10.2533/chimia.2016.418 Chimia 70 (2016) 418–423 © Swiss Chemical Society

*Correspondence: Prof. S. Matilea

E-mail: Stefan.Matile @unige.chaDepartment of Organic ChemistryUniversity of Geneva, GenevabDepartment of ChemistryUniversity of Basel, BaselcDepartment of ChemistryUniversity of Zurich, ZurichdDepartment of Biosystems Science and Engineering(D-BSSE)ETH Zurich, Basela-dNational Centre of Competence in Research(NCCR) Molecular Systems Engineering

Interfacing Functional Systems

Yoann Cotellea, Nicolas Chuarda, Santiago Lascanoa, Vincent Lebrunb, Robin Wehlauchc,Nadine Bohnic, Samuel Lörcherb, Viktoriia Postupalenkob, Sai T. Reddyd, Wolfgang Meierb,Cornelia G. Palivanb, Karl Gademannc, Thomas R. Wardb, and Stefan Matile*a

Abstract: The objective of molecular systems engineering is to move beyond functional components andprimary systems, towards cumulate emergent properties in interfaced higher-order systems of unprecedentedmultifunctionality and sophistication.

Keywords: Anion-π interactions · Catalysis · Cellular uptake · Complexity · Dynamic covalent bonds ·Emergent properties · Molecular systems engineering · Multicomponent surface architectures ·Multifunctionality · Photosystems · Polymersomes · Proteins · Systems chemistry

Reflecting novelty and complexity ofthe field, molecular systems engineering(MSE) can be defined in different ways,fromdifferent points of view.[1]For an argu-ably simplifying definition based on inter-facing and emergent properties, functionalunits of free choice are taken as primarycomponents (Fig. 1). Independent of sizeand nature, primary components can besmall molecules (catalysts,[2,3] transport-ers,[3,4] chromophores,[5] vitamins,[6] bio-adhesives[7]), macromolecules (enzymes,proteins,[6,8] polymers[5,9]), supramolecules(protein oligomers,[6,8] polymersomes,[9]liposomes[3]), cells,[4,8] devices,[5,7] and soon. Interfacing of primary components –non-covalent, dynamic-covalent or cova-lent – produces primary systems. Primarysystemsarecharacterizedbyproperties thatare absent in the individual primary com-ponents, i.e. emergent properties. Systemschemistry focuses on primary systems (oneout of several possible definitions circulat-ing in the community). Primary systemshave also received significant attentionin the context of supramolecular chemis-try, although often more from a structural

than from a functional point of view. Thegeneral objective of molecular systems en-gineering is to move beyond the primarysystems and focus on the interfacing ofsystems with systems (or components)to afford coupled systems (or ‘interfacedsystems’, ‘systems of systems’, ‘complexsystems’, ‘higher-order systems’, etc.),characterized by new emergent properties.The simplest coupled system, a formallysecondary system, is thus by definition tri-functional with respect to the engineeringoperations applied. Continuing interfacingaffords tertiary systems, quaternary sys-tems, etc., with emergent properties andthus increasing multifunctionality and/orsophistication.

One of the simplest primary compo-nents of current interest in the NCCRMSEis nothing more than an aromatic surface(Figs 2 and 3). The function of interest ofthis primary component is the binding ofholes (oxidation), cations, cationic reac-tive intermediates or cationic transitionstates on π-basic surfaces and the bindingof electrons (reduction), anions, anionicreactive intermediates or anionic transi-

tion states on π-acidic surfaces.[2]Whereascation-π interactions in all different formsare very well documented, anion-π andionpair-π interactions are of current inter-est because they are almost unexplored infunctional systems.[2,10] For several goodreasons, naphthalenediimides (NDIs) suchas 1 offer the π-acidic surface of choice fora promising primary component (Fig. 2).Interfacing with a carboxylate base, a func-tional component, through a Leonard turnaffords the formal covalent primary system2 (Figs 2 and 3). The emergent propertyis catalysis of the Kemp elimination.[11]Covalent interfacing of primary system2 with a proline base, another functionalcomponent, through an extended turn af-fords a covalently coupled, formally sec-ondary system 3.[2] The emergent propertyis the catalysis of enamine addition to ni-troolefins, a much more important reactionthan the Kemp elimination catalyzed bythe primary system. Interfacing with chiralsulfoxides at the edge of the π-acidic sur-face yields the formally tertiary covalentcoupled system 4.[2] The emergent prop-erty is stereoselectivity, i.e. asymmetric

PrimaryComponent

PrimarySystem

Multifunctionality(Complexity, Sophistication)

Interfacing

EmergentProperties

Interfacing

EmergentProperties

SecondarySystem

Interfacing

EmergentProperties

EmergentProperties

TertiarySystem

QuaternarySystem

Molecular Systems Engineering (MSE)

Interfacing

(Non-Covalent,Dynamic-Covalent,

Covalent)

Fig. 1. A definition of molecular systems engineering based on interfacing, emergent propertiesand increasing multifunctionality and sophistication.

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are placed in the oligothiophene channelto drive holes away from the solid sur-face, whereas fullerenes with three, twoand one cyclopropane are interfaced todrive electrons toward the solid surface.[5]Transcribing one of the more complex les-sons from nature toward the materials sci-ences, the emergent property of the result-ing, formally tertiary coupled system 6 isthe nearly complete elimination of chargerecombination.[5]

Boronic ester exchange has been intro-duced recently for the interfacing of a thirdstack under neutral conditions with a thirdorthogonal dynamic covalent bond.[15]Compatible with structural diversity, emer-gent properties reported for the tertiarysystem 7 include sensing (polyphenols ingreen tea),[15,19] spectral tuning (plant flow-er anthocyanines) or the stabilization ofunstable structures (tritylium cations).[16]From there, future perspectives for MSEare as described for covalent systemswith the exception that special attentionto dynamic-covalent interfacing strate-gies might become particularly rewarding:Boronic ester exchange is so far not fullyorthogonal to hydrazone and disulfide ex-change,[7,15] and the fourth orthogonal or-ganic dynamic covalent bond remains to bediscovered.

For non-covalent MSE, streptavidin 8

polymerization under basic conditions.[12]The emergent property of the π-stackedchromophores in primary system 5 ischarge transport. Yellow NDIs with twoethoxy substituents in the core were usedin original SOSIP architectures becausetheir stacks are able to separate chargesand transport both holes and electrons, thesingle channels in primary system 5 weresufficient to generate photocurrent, i.e.convert light into current.

Orthogonal to disulfide exchange, hy-drazone exchange under acidic conditionsis used to add π stacks along the originalstacks in primary system 5.[14] The result-ing secondary system 6 contains co-axialchannels that transport holes and electronsseparately. Charge separation into these co-axial channels can be named as unifyingemergent property of double-channel pho-tosystem 6 that affects several functionalreadouts. Interfacing with orthogonal dy-namic covalent chemistry makes stack ex-change very straightforward and thus addsaccess to structural and functional diver-sity as another general emergent propertywith secondary system 6.

The integration of antiparallel redoxgradients into double-channel photosys-tems 6 can be considered as an interfacingprocess. In the example shown, domainsof EDOT acceptors and thiazole donors

catalysis with a formally tetrafunctionalsystem composed of a) a π-acidic surfaceto stabilize anionic transition states and re-active intermediates, b) a proline base toactivate the aldehyde substrate as enamine,c) a glutamic acid to protonate the nitro-nate intermediate, and d) chiral sulfoxidesto assure stereoselectivity.

One general objective within theNCCR MSE will be to continue inter-facing of coupled systems such as 4[2,12]with the challenge to cumulate significantemergent properties beyond simple addi-tivity. Limited only by our imagination,functional components or systems con-ceivable for interfacing reach from addi-tional simple but meaningful functionalgroups to solid surfaces,[5,13–17] proteins,[6]polymersomes,[9] liposomes,[3] cells,[4] andso on. Success with MSE will ultimatelybe judged from the significance, practicalor conceptual, of the emergent propertiesobtained.

Dynamic covalent bonds are most at-tractive for systems interfacing becausethey can be reversible like non-covalentbonds and, under different conditions, existas irreversibly as covalent bonds.[4,5,13–17]For systems interfacing, this dual naturepromises access to self-sorting, self-heal-ing, adaptability, templation, amplification,replication, transcription, and so on.[18]

These expected advantages of dynamic-covalent chemistry for systems engineer-ing have been validated with multicompo-nent photosystems on solid surfaces (Figs4 and 5).[5,13–17]A chromophore is taken asa primary component with absorption andemission as intrinsic properties. The align-ment of these primary components in ori-ented π stacks on conducting solid oxidesurfaces affords primary system 5 (Fig. 4).The interfacing is achieved with SOSIP,a recently introduced method that oper-ates by ring-opening disulfide-exchange

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Fig. 2. Covalent coupled systems: A π-acidic aromatic surface 1 as primary component (blue; primary function: anion binding) is interfaced with acarboxylate to give primary system 2 (emergent property: catalysis of Kemp elimination (red arrows), an amine for secondary system 3 (emergentproperty: catalysis of enamine addition) and sulfoxides for tertiary system 4 (emergent property: stereoselectivity) with four distinct, covalently inter-faced components contributing to function (a-d). Compare Fig. 3 for explicit systems analysis.

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Interfacing

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Component

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Amine

SulfoxidesMSE

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Secondary System

Tertiary System

Fig. 3. Covalent coupled systems analyzed in the context of molecular systems engineering.Compare Fig. 2 for structures and Fig. 1 for definitions.

420 CHIMIA 2016, 70, No. 6 NCCR MoleCulaR SySteMS eNgiNeeRiNg

dividual characters of the homopolymersdomain yield a fluidic (PDMS) but robust(PMOXA) membrane.[23] Despite the hy-drophobic mismatch, the polymer mem-brane of these compartments represents anexcellent platform for membrane proteins,synthetic pores or bio-pores interfacing.Polymersomes or liposomes equippedwith membrane proteins, synthetic poresor photosystems are secondary systems(14).[3,24–27] For example, the insertion ofthe ion selective bio-pore gramicidin intoPMOXA-b-PDMS-b-PMOXA polymer-somes allowed H+, Na+ or K+ ions to passthrough the membrane and quench thefluorescence of encapsulated pyranine.The ion-dependent variation of the fluo-rescence intensity emerges from interfac-ing polymersomes with fluorophores, andbiopores.[25]

The combination of pores with mo-lecular recognition results in blockage, li-gand gating and, ultimately, conceptually

innovative catalysts that run new-to-naturechemistry within cells to engineered nucle-ases that control gene expression.

Other marvelous primary componentsfor non-covalent MSE are amphiphilicblock copolymers. Composed of covalent-ly linked hydrophobic and hydrophilicpolymer domains, they self-assemble inaqueous environments into a variety ofarchitectures, such as micelles, nanotubesor vesicles. In particular, amphiphilic di-and tri-block copolymers poly(2-methyl-2-oxazoline)-b-poly(dimethylsiloxane)-b-poly(2-methyl-2-oxazoline) (PMOXA-b-PDMS-b-PMOXA, 12) with appro-priate hydrophobic-to-hydrophilic ratioself-assemble into primary systemscalled polymersomes 13 (Figs 8 and 9).Complementary to liposomes formed bybiological lipids, polymersomes representan important platform for development ofreaction spaces at the nanoscale in MSE.During the membrane assembly, the in-

is a privileged, exceptionally versatileprincipal component (Figs 6 and 7).[6] Itis a tetrameric protein with four identical,extremely strong binding sites for biotin.Attached to biotin, organometallic cata-lysts for new-to-nature reactions have beensuccessfully interfaced with the protein.Moreover, mutant libraries of streptavidinhave been introduced as an exceptionallypowerful tool to screen the resulting pri-mary systems 9 for emergent propertiessuch as asymmetric catalysis, i.e. stereo-selectivity.[6,20,21]

Alternatively, streptavidin has beenequipped with transporters such as cell-penetrating poly(disulfide)s (CPDs).[4,22]The resulting primary systems 10 turnedout to enter cells as easily as expected.Understood structural modifications of theCPDs have been applied to direct the strep-tavidin to specific intracellular targets suchas the nucleoli. The emergent property ofnon-covalent primary system 10 composedof streptavidin and CPDs can thus be con-sidered as directional access to intracellu-lar compartments, or simply uptake.

The interfacing of streptavidinwith twodifferent biotin conjugates provides ac-cess to non-covalent secondary systems.[4]This possibility has been exemplified withcomplex 11 composed of streptavidin,biotinylated CPDs plus a biotinylated red-emitting fluorophore as a model substrate.The result were red-fluorescent nucleoli.These findings identified biotin-streptav-idin-based secondary systems like 11 asexcellent engineering tools to interfacecells with any object of interest within theNCCR MSE. Promising topics reach from

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Fig. 4. Dynamic-covalent coupled systems: A chromophore as primary component (primary function: absorption, emission) is engineered into prima-ry system 5 (interfacing: disulfide exchange (red), emergent property: charge transport), secondary system 6 (interfacing: hydrazone exchange (ma-genta), emergent property: charge separation) and tertiary system 7 (interfacing: boronic exchange (violet), emergent property: sensing). CompareFig. 5 for explicit systems analysis.

Component

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Double Channel

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System

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Charge Separation

a) Charge Recombinationb) Sensing

Interfacing

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Disulfide Exchange

Hydrazone Exchange

a) Sequential Exchangeb) Boronic Ester Exchange

Fig. 5. Dynamic-covalent coupled systems analyzed in the context of molecular systems engi-neering. Compare Fig. 4 for structures and Fig. 1 for definitions.

NCCR MoleCulaR SySteMS eNgiNeeRiNg CHIMIA 2016, 70, No. 6 421

specificity of the interfacing sites. To thisend, blends of two primary components,non-functionalized and tris(nitrilotriaceticacid) functionalized poly(butadiene)-b-poly(ethylene oxide) polymers, were as-sembled in aqueous conditions. Theseprimary systems, trisNTA decorated poly-mersomes 21, exhibited emergent metalion mediated binding affinity to variousproteins/peptides, yielding functional sec-ondary systems 22.[35] These basic studiesenable reliable step-by-step engineering ofcatalytic nanoreactor networks as part ofthe roots of molecular factories.

With cells or devices as primary com-ponents, similar systems analysis of real-ized examples and systems engineering forfuture coupled systems can be easily for-mulated. For instance, the systems analysismade for cell-penetrating red-fluorescentsecondary systems 11 could also be madewith cells instead of streptavidin 8 as pri-mary component (Figs 6 and 7).[4]

Arguably, chemical metabolism pres-ents the most complex primary componentthat is interfaced by a plethora of path-ways resulting in the primary system ofa cell, with the emerging property of life.Interfacing chemical catalytic units withthis primary system will generate complexsecondary systems that will leverage thebiosynthetic potential of organisms by in-troducing new-to-nature functionality, andby generating chemical reactions not yetfeasible in biological systems per se. In ad-dition, it should be pointed out that thesesecondary systems should be generated denovo, by assembling molecular new-to-na-ture components therefore allowing for un-precedented functionality not constrainedby genome modification of the underlyingprimary system. A number of interfacingstrategies can be envisioned on a molecu-lar level, and a bio-inspired approach forselection and optimization suggested theuse of catechols as building blocks.[7]

or trastuzumab yielding primary systemscapable of interfacing with cell surfaces orpatterning of surfaces.[32]

The encapsulation of multiple enzymesworking in polymersomes equipped withOmpF allowed the creation of the first ar-tificial peroxisomes 17. Up-taken by cells,the artificial peroxisomes successfullydetoxified in situ superoxide radicals andrelated H

2O

2.[33] A more complex scenario

can be envisioned when different nanore-actors are interfaced to support complexcascade reactions, able to serve as core ofmolecular factories 18.

As an alternative to block copolymers,copolymers allow for molecular interfac-ing with emergent spatial organizationof the interfacing sites due to function-al group patterning along the polymerchains. The primary component poly(N-isopropylacrylamide-co-tris-nitrilotriac-etic acid acrylamide) 19 was complexedwith metal ions to facilitate site-specificreversible molecular recognition (Fig. 10).Interfacing His

6-GFP with Zn2+-19 modu-

lated the number of proteins per poly-mer chain 20.[34] To move a step furtherin MSE, individual nanoreactors shouldbe interfaced to form well-defined multi-functional networks. The emergent prop-erties of such networks could be tunedby varying the number and the molecular

innovative stimuli-responsive membranesor sensors.[3,19,23,25–28] The interfacing ofpores in polymersomes and liposomeswithenzymes and synthetic catalysts leads totertiary systems 15–17.[3,29,30] Such tertiarysystems may interface with themselves toyield quaternary systems 18 or with cellsin an analogue manner to yield simple ar-tificial organelles.[29] In a next round of in-terfacing, the pores or membrane proteinsin a nanoreactor can be genetically/chemi-cally modified to trigger in situ reactionsor possibly release the cargo ‘on demand’.OmpF, a bacterial porin, was chemicallymodified to accept a hydrazine to yielda hydrazone bound fluorophore, whichblocked the pore. Interfacing this modifiedporin with polymersomes containing en-capsulated horse radish peroxidase yieldedpH-triggered nanoreactors.[30]

Assemblies from polymer blends ofdifferently functionalized chains promotethe attachment of a vast variety of mol-ecules for targeting, catalytic networkformation, as well as surface anchoring.For example, nanoreactors containingpenicillin acylase were immobilized onamine-functionalized silicon surfaces toyield surfaces with emergent antimicro-bial properties.[31] In another approach,polymersomes were functionalized withspecific molecules such as anti-biotin IgG

Interfacing

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Component

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a) Transporterb) Catalyst

a) FluorophoreMSE

System

-

Primary System

Secondary System

Emergent Property

-

a) Cellular Uptakeb) Stereoselectivity

a) Cellular Imaging

Fig. 7. Streptavidin as primary component for non-covalent systems engineering. Compare Fig. 6for structures and Fig. 1 for definitions.

HNO

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O

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PenetratingPolydisulfides

(CPDs)

Primary Systems

8

Streptavidin

9

BiotinylatedCatalyst

BiotinylatedRed-

FluorescentModel

Substrate Secondary System

PrimaryComponent

Fig. 6. Non-covalent coupled systems: Interfacing of streptavidin as non-covalent primary component 8 (primary function: binding) with transition-metal catalysts yields artificial metalloenzymes as primary system 9 that catalyze new-to-nature reactions. Interfacing with CPDs affords primarysystem 10 that can enter into cells. Interfacing with CPDs and a fluorescent model substrate affords the secondary system 11 as cell-penetratingfluorescent probe. Compare Fig. 7 for explicit systems analysis. Insert: X-ray structure of an artificial imine reductase based on the biotin-streptavi-din technology (PDB code: 3PK2).[21]

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Recognizing the potential of siderophore-derived catechols for surface functional-ization,[36] we developed this platform fora variety of applications, from antimicro-bial surfaces to neuritogenic materials.[37]We think that this bio-inspired catecholateplatform has tremendous potential for in-terfacing functional systems and thus in-troducing new-to-nature functionality inliving systems.

Overall, the unifying theme among theanalyzed examples for covalent, dynamic-covalent and non-covalent coupled systemsis the interfacing of functional componentsand the emerging properties obtained. Theobjective of the NCCRMSE is to drive thiscumulative interfacing to the extreme andachieve unprecedented levels of sophis-tication and multifunctionality. Callingfor extraordinary creativity, no one reallyknows where this cumulation of emergentproperties beyond the classical systemschemistry will lead to. Ultimately, MSEis expected to provide access to processesthat a) are important and b) cannot be re-alized otherwise, with more conventional

approaches. Moreover, lessons learned onthe way will help improve on some cur-rent limitations such as the ability to syn-thesize not small molecules but large andcomplex molecular architectures with highprecision, to have more than two orthogo-nal dynamic covalent bonds available forinterfacing, to deliver whatever is needed

into cells, and so on, not to speak of all theanalytical challenges involved. Interfacingdifferent functional systems from differ-ent disciplines with different expertise,molecular systems engineering calls forcollaborative work. One of the most im-portant objectives of the NCCR MSE is tohelp initiate these decisive collaborations.

Fig. 10. Non-covalent metal coordinated MSE: Interfacing of functionalized polymers 19 or polymersomes 21 as non-covalent primary systems.Interfacing these primary systems with fluorescent His6-tagged proteins 20 (orange) via metal coordination (blue) yields secondary systems 20, 22with emergent fluorescent properties.

Fig. 8. Non-covalent coupled systems: Amphiphilic polymers 12 or phospholipids as primary components self-assemble into polymersomes orliposomes yielding primary systems 13. Interfacing of polymersomes with membrane proteins yields secondary systems 14, in which ions andmolecules are able to cross the membrane through the pore. Further interfacing with catalysts, enzymes or catalytic pores affords nanoreactors astertiary systems 15–17. Interfacing of two nanoreactors is expected to yield quaternary systems 18. Interfacing tertiary systems 17 with cells lead toartificial organelles as quaternary systems. Compare Fig. 9 for explicit systems analysis.

Fig. 9. Polymersomes and liposomes as primary systems for non-covalent systems engineering.Compare Fig. 8 for examples and Fig. 1 for definitions.

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AcknowledgementsWe thank all past and present cowork-

ers and collaborators for their contributionsto this research, and the National Centre ofCompetence in Research (NCCR) MolecularSystems Engineering, administered by theSwiss NSF, for financial support. Gratefullyacknowledged is additional financial supportfrom the Universities of Geneva (SM), Basel(TW, CP, WM) and Zurich (KG), the ETHZ(SR), and the Swiss NSF.

Received: March 20, 2016

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