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Cite this:DOI: 10.1039/c6cs00176a

Peptide self-assembly: thermodynamicsand kinetics

Juan Wang,a Kai Liu,ab Ruirui Xinga and Xuehai Yan*ac

Self-assembling systems play a significant role in physiological functions and have therefore attracted

tremendous attention due to their great potential for applications in energy, biomedicine and nanotechnology.

Peptides, consisting of amino acids, are among the most popular building blocks and programmable

molecular motifs. Nanostructures and materials assembled using peptides exhibit important potential for

green-life new technology and biomedical applications mostly because of their bio-friendliness and

reversibility. The formation of these ordered nanostructures pertains to the synergistic effect of various

intermolecular non-covalent interactions, including hydrogen-bonding, p–p stacking, electrostatic,

hydrophobic, and van der Waals interactions. Therefore, the self-assembly process is mainly driven by

thermodynamics; however, kinetics is also a critical factor in structural modulation and function

integration. In this review, we focus on the influence of thermodynamic and kinetic factors on structural

assembly and regulation based on different types of peptide building blocks, including aromatic

dipeptides, amphiphilic peptides, polypeptides, and amyloid-relevant peptides.

Introduction

Self-assembly is ubiquitous in natural systems, such as the DNAdouble helix and protein folding, associated with a variety ofnon-covalent interactions. It not only plays a vital role inphysiological functions, but also provides an excellent sourceof inspiration for designing functional, dynamic and reversible

structures and architectonics over different length scales. Peptides,as popular biologically-inspired building blocks, have attractedincreasing attention with respect to the creation of advancedmaterials and applications in newly-occurring nanotechnologyand biomedicine. They have many attractive advantages, such asinherent biological origin, structural programmability, goodbiocompatibility and biodegradability, low immunogenicity,and versatile functionality, as well as easy availability and cost-effectiveness.1–5 Peptide self-assembly, as a fabrication strategy,can be utilized for creating various architectures from nanotubeson the nano-scale to fiber bundles on the macro-scale, with variousconformations, such as b-sheet and a-helix. The self-assembly ofpeptides over different length scales has outstanding potential

a State Key Laboratory of Biochemical Engineering, Institute of Process Engineering,

Chinese Academy of Sciences, Beijing 100190, Chinab University of Chinese Academy of Sciences, Beijing 100049, Chinac Center for Mesoscience, Institute of Process Engineering,

Chinese Academy of Sciences, Beijing 100190, China. E-mail: [email protected];

Web: http://www.yan-assembly.org/

Juan Wang

Juan Wang received her PhD degreein chemistry from the Beijing NormalUniversity in 2014 and then startedpost-doctoral research at the Instituteof Process Engineering (IPE), CAS,under the supervision of Prof. Yanin the same year. Her researchinterests are mainly focused on thedesign, assembly and mechanisms ofpeptide-based nanostructures andmaterials.

Kai Liu

Kai Liu received his BS degree fromthe Yanshan University in 2012and is currently a PhD student atthe Institute of Process Engineering(IPE), CAS, under the supervision ofProf. Yan. He is conducting researchon the peptide-modulated self-assembly of photoactive molecules,including controlled hierarchicalorganization and the thermo-dynamic and kinetic aspects ofthe formed structures.

Received 4th March 2016

DOI: 10.1039/c6cs00176a

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applications in areas such as energy, biomedicine, and nano-technology.6–10 For instance, peptide materials may be regardedas excellent nanoarchitectonics,11–14 aiming at the constructionof complex functional systems and devices, which have moreopportunities for getting close to biosystems. Although there arenumerous studies on the applications of peptide assembly, thethermodynamic and kinetic properties of peptide assembly arestill in their infancy.

Peptide assembly is a spontaneous thermodynamic andkinetic driven process, based on the synergistic effect of variousintermolecular non-covalent interactions, including hydrogen-bonding, p–p stacking, electrostatic, hydrophobic, and van derWaals interactions.15 As shown in Fig. 1, the synergistic effect ofthese non-covalent interactions determines the thermodynamicstability and the state of minimum energy of the ultimately formed

nanostructures. Owing to their relatively weak nature, however,the pattern of these non-covalent interactions can be preciselyand reasonably modulated with various kinetic parameters,including pH, temperature, counter-ions, concentrations, andsolvents. For selected kinetic parameters, assembled structurescan be trapped in metastable states. Without the interventionof kinetic parameters, these metastable structures will finallygrow into the thermodynamically favored state. Therefore, acompetitive relationship between kinetic and thermodynamicstates of assembly provides the possibility of transformationfrom thermodynamic control to kinetic control. The kineticcontrol of peptide assembly is not only important for understandingthe assembly mechanisms, but also enables the creation of dynamicmaterials. In this review, we focus on thermodynamic andkinetic contributions to the assembly of different types ofpeptides, including aromatic dipeptides, amphiphilic peptides,polypeptides, and amyloid-relevant peptides.

Interactions responsible for peptideself-assembly

The synergism and cooperativity of various non-covalent inter-actions in self-assembly have been reviewed recently.16 Thesenon-covalent interactions are essential to determine the thermo-dynamically stable structure. In fact, with the cooperativity ofvarious non-covalent interactions, single amino acids, such asphenylalanine and serine, can form oligomers, metaclustersand even toxic fibrillar aggregates in solution, implicating themechanism and growth trends of peptide assemblies.17–19

Herein, in order to understand and control the self-assemblyof peptides, we focus on five types of non-covalent interactionstaking part in this process: hydrogen-bonding, p–p, electro-static, hydrophobic, and van der Waals interactions. The kineticstructural control is always accomplished by many factors, includingpH, temperature, and electrolyte concentration. We also discuss

Fig. 1 Schematic of the assembly pathways under thermodynamic andkinetic control. Note: under thermodynamic control, the final structures, suchas crystal, nanotubes (NT), and nanowire (NW), are in the state of minimum freeenergy (orange solid line). If kinetic control (e.g. pH, temperature) intervenes,the structure can be trapped in a metastable state, including gel (fibers),nanosphere (NS), ribbon, and NW (blue solid line). These metastable structurescan further grow into the thermodynamically favored state (blue dashed line). Itshould be noted that the relative energy of each structure does not present anabsolutely accurate value, e.g. the energy of the NS may be lower than that ofcrystals in some systems. All structures probably interconvert under certainkinetic controls.

Ruirui Xing

Ruirui Xing received her bachelor’sdegree at Yanshan University in2012 and then started her MS-PhD study there. She is currentlypursuing her PhD as an exchangestudent at the Institute of ProcessEngineering (IPE), CAS, under thesupervision of Prof. Yan. Herresearch interests are focused oninjectable self-assembling peptide-and protein-based hydrogels fordrug delivery towards antitumortherapy. Xuehai Yan

Xuehai Yan obtained his PhD inchemistry at the Chinese Academyof Sciences (CAS) in 2008. Afterthat, he moved to the Max PlanckInstitute of Colloids and Interfacesin Germany for post-doctoralresearch as an Alexander vonHumboldt fellow. In 2013, hebecame a professor at the Instituteof Process Engineering (IPE), CAS.He is a vice director at the Centerfor Mesoscience, IPE, CAS. He is aboard member of Colloids &Surfaces A. His research interests

are mainly focused on the chemistry and materials of peptide self-assembly, mesoscale mechanisms, biomimetic protocells andfunctional architectonics for biomedicine and bioenergy.

Review Article Chem Soc Rev

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the influence of these different factors on the non-covalentinteractions.

Hydrogen-bonding

Hydrogen-bonding is an important driving force for structuralorganization in biological systems. Peptides, as one of theimportant biomolecules, provide an abundance of hydrogen-bond-formation sites, including amide groups in the peptidebackbone and amino and carboxyl groups in the sidechains.Hydrogen bonding plays a significant role in the formation andstabilization of the peptide’s secondary structure and proteinfolding. For example, in the process of protein fibril formation,which is thought to be a major element in Alzheimer’s diseaseand other degenerative disorders, water-assisted hydrogen-bonding is believed to be the critical factor in self-assembly.20,21

Actually, among different non-covalent interactions, hydrogenbonding is probably the most important in peptide self-assembly. The selectivity and high directionality of hydrogen-bonds can induce the conversion of peptides into diverse1-dimensional (1-D), 2-D, and 3-D nanostructures. The strengthsof hydrogen bonds are mainly 5–10 kT (B10–40 kJ mol�1) perbond at 298 K.22

p–p interactions

p–p stacking can drive the peptide self-assembly, especiallyfor p-conjugated peptides, such as aromatic peptides. Theinteractions of p–p stacking can induce directional growth,and they are also very robust in water because of the limitedsolubility of molecules containing aromatic groups. The p–pstacking is also a more distinct driving force in pure organicsolvents, such as toluene. This is because the solvent effects canmake the p–p stacking more dominant, as proven in our previousstudies.23

Hydrophobic

Hydrophobic interactions, which have few directional constraints,are well known as one of the driving forces in surfactant systems.Apolar molecules cannot interact favorably with a water molecule.When many amphipathic molecules are introduced into water, thehydrophobic parts of these molecules try to aggregate to minimizetheir surface area in contact with water, leaving the hydrophilicparts exposed to water. In other words, hydrophobic interactionsare stabilized due to favorable entropy rather than favorableenthalpy.24 It was found that, under pure hydrophobic inter-actions, peptides favored the formation of micelles rather than1-D nanofibers.25 In a salt-triggered self-assembly process, therole of hydrophobic driving forces can be significantlyenhanced because of charge-screening effects.26 Moreover,hydrophobic forces are important for the rational design ofpeptide amphiphiles.

It is worth pointing out that the aromatic residues of peptidebuilding blocks may play roles through either hydrophobicinteractions or p–p interactions: the organization mode ofaromatic residues in the hydrophobic interactions is commonlydisordered, while in p–p interactions, it is well-organized andordered.

Electrostatic bonds

Interaction between charges is another well-known type of non-covalent interaction used for self-assembly, such as layer-by-layerassembly.27 Electrostatic bonds based on Coulombic attractionsbetween opposite charges lead to the formation of ion-pairs. Thestrength of an ionic bond is approximately B500 kJ mol�1 orB100 kT, much stronger than that of a hydrogen bond.22 Unlikethe key role of hydrogen-bonding and hydrophobic interactions,electrostatic interactions are usually employed to induce structuralspecificity for charged peptides. The importance of electrostaticinteractions for the formation of nanostructures has been wellreviewed.28,29

van der Waals interactions

The effective range of van der Waals forces can reach hundredsof angstroms, and the strength of a typical van der Waals bondis about B5 kJ mol�1 or B1 kT, weaker than that of a hydrogenbond.22 van der Waals forces, such as the interaction betweenaliphatic tails in peptide amphiphiles, provide an importantcontribution to various non-covalent interactions and are ubiquitousin assembly systems. However, only a few examples employvan der Waals interactions as a predominant force for thecontrol of self-assembly.30 van der Waals interactions arisefrom fluctuations of the electron distribution of two closelyspaced molecules. They can be treated as a type of instantaneouselectrostatic interaction.

Synergistic effect of the non-covalent interactions

Rather than using one single type of interaction, the combinationof different types of non-covalent interactions is by far the mostefficient approach to achieve stable self-assembly for the fabricationof structures. For example, by using molecular dynamics (MD)simulations, Stupp et al. have shed light on the process of peptideself-assembly and found a ‘‘phase diagram’’ linking the hydrogen-bonding strength and hydrophobic attraction strength.25

Effect of ‘‘kinetic factors’’ on ‘‘thermodynamic interactions’’

Temperature is a powerful factor in varying hydrogen-bondingand hydrophobic interactions. Elevated temperatures mayweaken or break the intermolecular hydrogen-bonds butincrease the hydrophobic effect. Properties of solvents have ahuge influence on the solvation effect of peptide molecules. Forinstance, the pH of the solution affects the competing solvationbetween donor and acceptor sites of hydrogen-bonds. Salt ionsmay capture the solvent molecules by solvation, resulting in adecrease in the hydrogen-bonding of peptide and solvents.Moreover, salt effects, including pH, type of salt ion, and ionicstrength of the solution, also have great impact on electrostaticinteractions. A typical example to state the effect of variouskinetic factors on thermodynamic interactions is the work ofKim and Ihee.31 They found that hydrogen-bonding betweenwater and diphenylalanine (FF) molecules played a role in theassembly, and induced a structural transition between NW andNT by altering the concentrations of FF, temperature, ions, andsonication. One can see that all these factors have effects on the

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hydrogen-bonding: temperature and sonication decrease hydrogen-bonding, the FF concentration adjusts the ratio of hydrogen-bondingbetween each FF and water molecules, and ions can reduce thefree water, presumably weakening the hydrogen bondingbetween peptides and water molecules. The compromise andbalance of hydrogen bonds influenced by these kinetic factorsenable structural regulation between NW and NT.

Diphenylalanine-based aromatic peptides

Many short peptide motifs containing aromatic groups havebeen unraveled to self-assemble in aqueous solution. FF, afragment of Alzheimer’s b-amyloid polypeptide, is one of thesimplest and most common recognition motifs for molecularself-assembly.32 It is a suitable candidate to study structureformation and regulation, due to its simple molecular structureand distinct intermolecular interactions. Moreover, FF hasbeen found capable of self-assembly into a variety of complexarchitectures,33 such as hexagonal microtubes (NTs),34 nano-wires (NWs),31 and fibers.35

Thermodynamics and kinetics of formation of NTs, NWs andnanospheres

Reches and Gazit first discovered that the FF peptide can self-assemble into well-ordered hollow NTs.32 Despite the potentialapplications and growing studies on FF-based materials, littleis known about the mechanism of such a self-assembly. Rechesand Gazit highlighted the important role of aromatic stackingand found that ion-pairing interactions are not a necessarydriving force to form NTs.36 A recent systematic MD study byShell et al. has further unraveled the balance of hydrogenbonds, electrostatic, and side chain hydrophobic interactionsin the first stages of FF assembly. The results revealed that acrystalline fraction of NTs is stabilized by hydrophobic inter-actions between side chains, but that electrostatic interactionsbetween termini that form salt bridges steer their backbonesinto a more ordered state.37 Bowers et al. reported that watermolecules play a key role in the stable FF oligomers.38 Recently,Levin and Mason et al. investigated the formation kinetics ofBoc-FF-based NTs, and the results revealed that, before for-mation of an NT, the Boc-FF monomers coalesce into nano-spheres through Ostwald’s step rule. Then, the nanospheresundergo ripening and finally convert into NTs (Fig. 2a). Differ-ential scanning calorimetric measurements indicate that thethermodynamic stability of the tubular phase is higher thanthat of the spherical phase (Fig. 2b).39

FF-based NTs are generally prepared by diluting a stocksolution of FF in a good solvent (i.e. hexafluoroisopropanol,HFIP) with a poor solvent (i.e. water). The formed NTs arerobust and stable in boiling water and even in some organicsolvents.40 Compared with the other structures, such as NWsand nano-vesicles, FF-based NTs may be the thermodynamicallymost stable structure in water, i.e. the formation of NWs (or nano-vesicles) and NTs seem to be under kinetic and thermodynamiccontrol, respectively.31,39 This morphology of FF nanostructures can

be rationally designed, controlled, and interconverted by incorpora-ting many parameters to change the kinetic parameters.31,41–46 Forexample, Yan and Li et al. reported that a cationic FF can take partin an interesting spontaneous transformation of NTs into sphericalvesicle-like structures during a solution dilution process, and themechanisms of the transition can be described by Delaunay’smodel.43 Kim and Ihee et al. also easily obtained both NW andNT morphologies just by altering the concentrations of FF, andX-ray diffraction revealed that hydrogen-bonding between waterand FF molecules plays a role in the structural transition.31

A MD study also revealed that the assembly pathways of FF areconcentration-dependent, and the formation of different nano-structures results from the balance between peptide–peptide andpeptide–water hydrogen-bonding interactions.47 Solvent properties,such as polarity and ability of hydrogen-bonding, will directlyinfluence local interactions of peptide self-assembly on the mole-cular level.48 The solvent-dependent structural transition in thepeptide-based building blocks has been confirmed widely.23,39,48–52

In one typical example previously studied by Yan and Li et al., FFundergoes self-assembly, forming flower-like microcrystals in polarethanol but long nanofibrils in non-polar toluene. It is believed thatthe reason for the nanofibril formation is that addition of toluenebreaks the balance between hydrophobic and hydrogen-bondinginteractions, and p–p stacking is dominant during the assemblyprocess.23 Another case recently reported by Qi et al. showed thatthey could control the diameter and wall thickness of the NTs bymodulating the degree of supersaturation of the FF and the watercontent.34

Thermodynamics and kinetics of nanofibers and gels

Nanofibers/nanobelts with b-sheet structures are another typeof important morphology of peptides. Escuder and Miravet

Fig. 2 (a) SEM images and schematic depiction of structural transitionsand (b) free energy changes during the phase transition observed in theBoc-FF system. Reproduced with permission from ref. 39, Copyright 2014,Macmillan Publishers Limited.


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obtained insight into the thermodynamics and kinetics of thefibrillation of FF-based tetrapeptides. They found that dimerformation is the kinetic bottleneck and rate-determining stepof the fibrillation process.53 The nanostructures of fibers can berationally designed by altering many kinetic parameters. Forexample, FF NTs can undergo a transition into fiber structuresupon heating.54 Wang and Qi et al. reported that ferrocene-modified FF (Fc-FF) changed the conformation of the secondarystructures from flat b-sheets into twisted b-sheets, and thedetailed diameters of the twists can be controlled by counter-ions, temperature and solvents (Fig. 3a and b). The drivingforces for forming twist structures are the balance of p–pstacking, hydrogen bonding, and the chirality of Fc-FF mole-cules. In this study, temperature is a typical kinetic controlfactor: the platelet crystal is the thermodynamically stable statefor Fc-FF, while at different temperatures, the structural transi-tion proceeds along a different pathway (Fig. 3c).55 In our recentstudies, we found that, unlike the microspheres induced by FF(Fig. 4),35 porphyrins self-assemble into long-range order and alignin fiber bundles with the cooperation of a charged dipeptide (L-Lys-L-Lys, KK; Fig. 4). In terms of Onsager theory, we attribute theformation of bundles to the competition between rotational andtranslational entropy (Fig. 4).56 These peptide-modulated self-assembly microspheres and bundles can be used in biomimeticlight-harvesting systems.57

On the other hand, physical gels, consisting of peptide fibersand solvents, are novel soft materials and display remarkablepotential for application in bionanotechnology. Moreover, thegels offer a simple model system for studying the complexproblem of peptide self-assembly. There are already severalimportant reviews on the studies of peptidic gels.58–60 Forexample, Gazit et al. summarized the gel design of peptidebuilding blocks.61 Adams et al. reviewed the relationshipbetween mechanical properties and kinetic conditions of gelformation.62 Cameron et al. focused on the interactions andfactors, such as pKa, that determined gel formation.63 The

current debate on the driving forces of gel formation focuses onhydrogen bonding, hydrophobic interactions, and p–p stacking.These interactions are all crucial factors in gelation.64 It seemsthat each of the interactions can be dominant in certainsystems.63,65 For instance, our previous studies supported thetheory that FF forms gels with nanofibril structures in puretoluene due to synergy between hydrogen bonding of the FFmain chain and the p–p stacking of aromatic residues, and thelatter p–p stacking interactions may be predominant.23

Recently, we also found that trace amounts of hydrogen-bond-forming solvents play a key role in the formation of fibrilsand gels in dichloromethane (Fig. 5).66 A gel is always treatedas a kinetically trapped structure. The nucleation and growthof gelation is strongly kinetics dependent. For instance,the micro-structures of FF-based organogels can changefrom nanofibers to nanobelts with heat treatment or waterinduction.67 Ultrasound is an effective kinetically-controlledmethod to reconfigure nanostructures by assisting peptidemolecules to overcome energy barriers of intermolecular non-covalent interactions. As reported in the work of Ulijin, tripep-tides can form anisotropic gels by an in situ ultrasonic trigger.68

There are also many studies on the kinetic control as well asthe influence of different kinetic factors on gel formation.69–73

Yet, the thermodynamic nature of gelation is still not fullyunderstood.

Fig. 3 (a) Molecular structure of Fc-FF, (b) rational design and SEM imagesof nanostructures, and (c) schematic diagram of kinetically controlled self-assembly of Fc-FF by temperature. Reproduced with permission fromref. 55. Copyright 2015, American Chemical Society.

Fig. 4 (a) Proposed mechanism for microsphere and fiber bundle formationinduced by different dipeptides. Confocal image of (b) microspheres and(d) fiber bundles showing red photoluminescence. (c) SEM image of micro-spheres, and (e) TEM image of bundled fibers. Reproduced with permissionfrom ref. 35 and 56, respectively. Copyright 2014 and 2015, Wiley.


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Crystallization vs. gelation in self-assembly: thermodynamicsor kinetics

The competition between crystallization and gelation is always akey issue in self-assembly. Non-covalent interactions and variousfactors, such as pKa, can determine whether the gel forms.63 Itseems hard to predict the priority selection of a molecule: crystal-lization or gelation? The crystal state is an organized moleculararrangement over large distances with well-ordered packing and ahigh number of stabilizing interactions. Adams et al. succeeded in

crystallizing one dipeptide directly from the gel. They found thatthe fiber structure in the gel is principally different from that in thecrystal, and the lattice packing is less condensed than in thecrystal.64 However, this is not the whole answer. To evaluate whichstructure is more stable, the thermodynamic parameter, freeenergy, is a good indicator. Generally, crystals should be in thethermodynamic minimum state, and a gel is a kinetically trappedmetastable state. Actually, it is found that the energy of the gelstate may also represent a thermodynamic minimum.74 Recently,Ulijn and Tuttle et al. introduced a simple prism packing modelwith varying solvophilic and solvophobic properties in each face ofthe prisms, to calculate the free energy of the system. This modelhas been successfully applied to the Fmoc-FF gelator, in which theformed 1-D fibers represent thermodynamic equilibrium(Fig. 6a).74 This is a typical example in which the peptide gel is athermodynamically favorable assembling structure.

On the other hand, apart from the solvophilic and solvophobicproperties of peptides, the properties of solvents are also key todetermining and modulating the free energy and gelation of thesystems.75 Rogers et al. illustrated in a detailed way the importantrole of solvent properties in gel formation.76 The solubility para-meters of solvents, such as Hansen solubility parameters (HSP),which include three important parameters, i.e. dispersion (dd),dipole–dipole (dp), and hydrogen bonding (dh) interactions, playan important role in gel formation. The HSP can be used to classifythe gelator behavior in 3-D plots (Fig. 6b).77

Thermodynamics and kinetics of aligned structures on surfaces

The fabrication of ordered peptide chains on surfaces hasattracted increasing attention due to their potential applicationin bionanotechnology. Vapor deposition methods are commonlyused in preparing aligned structures on solid surfaces. Forinstance, Ryu and Park obtained uniform and vertically well-aligned NWs by changing the water activity in the vapor phase,78

as well as with the aid of aniline vapor at high temperatures.79

They suggested that the mechanism of NW growth is related tosurface-initiated nucleation from an initially amorphous film.Kern et al. demonstrated that intermolecular hydrogen-bondingmight be the major driving force for the formation of NWs or

Fig. 5 (a) Schematic depiction of a phase transition induced by traceamounts of solvent. Hydrogen-bond-forming solvents can induce FF toform fiber structures. SEM images of (b) FF/CH2Cl2, and (c) FF/CH2Cl2/ethanol systems. (d) AFM height image of the FF/CH2Cl2/ethanol system,and (e) corresponding height profiles along the green line, showing a fiberheight of approximately 15 nm. Reproduced with permission from ref. 66,Copyright 2016, American Chemical Society.

Fig. 6 (a) Schematic diagram of the free energy of different states. (b) The important role of solvent properties (HSP) in gel formation. Reproduced withpermission from ref. 74 and 77, Copyright 2016, American Chemical Society, and 2014, The Royal Society of Chemistry, respectively.


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chains on Cu surfaces.80 Moreover, Gazit et al. demonstratedthe self-assembly of large arrays of FF NTs using vapor depositionmethods. It has been suggested that the stacking interaction ofaromatic moieties provides a main energetic contribution anddirectionality for the initial interaction.81,82 Recently, they alsoutilized a solvent-free method, i.e. plasma-enhanced chemicalvapor deposition, to prepare FF-based nanostructures. Thedeposited nanostructures can be kinetically controlled by thespecific discharge parameters used during the deposition process(Fig. 7).83 In fact, the hydrophobicity index of the substrate is alsoan important factor influencing the assembly kinetics and the finalnanostructures of peptides.42

Aligned peptide structures can also be used as linkers tomodify other novel materials, e.g., an inorganic binding peptidewas utilized as a smart molecular linker to affect the assemblykinetics of quantum dots on a substrate.84 In a recent study,Sarikaya et al. investigated the adsorption behavior of a gold-binding peptide and obtained the kinetic and thermodynamicparameters to understand the binding of the peptide on surfaces.85

Amphiphilic peptides (APs)

Amphiphilic peptides (APs) are a class of molecules thatcombine the structural features of amphiphilic surfactants withthe functions of bioactive peptides. APs are known to assembleinto a variety of nanostructures, and the most well-known structureis 1D nanofibers with a cylindrical geometry. These nanostructuresare of great interest in many biomedical applications.

The self-assembly of APs has also been reviewed,4,86–88 butearlier reviews focused specifically on the preparation andapplication of AP nanostructures. The purpose of the followingsection is to provide insight into the thermodynamic as well askinetic factors of AP self-assembly.

The thermodynamic mechanisms of AP self-assembly

Because 1-D fibers can represent thermodynamic equilibrium,they may be a thermodynamically favorable assembly structurefor APs. In fact, AP molecules behave in some respect likeamphiphilic surfactants. There are charged amino acids in APmolecules; therefore, the assembly environment is more complexthan that of aromatic dipeptides. Apart from hydrogen-bonding,p–p, and hydrophobic interactions, electrostatic repulsion alsoplays an important role in driving the self-assembly process.89 Aspointed out by Stupp et al.: ‘‘among the four major energycontributions, hydrogen-bonding, p–p, and hydrophobic inter-actions all tend to promote the aggregation of AP molecules,whereas electrostatic repulsion favors disassociation of AP mole-cules. The final properties of assemblies reflect a delicatebalance of each energy contribution.’’86 They have also shedlight on the self-assembly process of APs by MD simulations, andobtained a ‘‘phase diagram’’ by combining the hydrogen bond-ing strength and hydrophobic attraction strength (Fig. 8).25,86

They found that ‘‘purely’’ hydrophobic interaction leads to micellestructures, while the ‘‘pure’’ hydrogen bonding interaction resultsin the aggregation of 1D b-sheets. The final assembly kinetics couldshow the synergistic effect of these non-covalent interactions.

The kinetic control of AP self-assembly

Although self-assembly is an energy-driven process, the regulationof the assembled structure is tuned by kinetic parameters.88,90–96

The kinetic factors actually influence the thermodynamic inter-actions between peptide molecules, as well as between peptidemolecules and solvents, as suggested in Section II on ‘‘Inter-actions responsible for peptide self-assembly’’.88,90–96 Stupp’sgroup has started many studies in this field. For instance, theyfound that through changes in pH and concentration, nano-belts can transform into twisted ribbons due to the break-up of

Fig. 7 SEM images of diphenylalanine nanostructures on (a) and (b) siliconwafer, (c) carbon electrode, and (d) PDMS. SEM images of nanostructuresgrown under different deposition conditions: (a) 250 Hz and (b) 500 Hz.Scale bar is 1 mm for all images. Reproduced with permission from ref. 83.Copyright 2014, American Chemical Society.

Fig. 8 Schematic phase diagram of AP assemblies. Reproduced withpermission from ref. 86, Copyright 2010, Wiley.


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the balance of electrostatic repulsions and hydrogen bondinginteractions.97 In addition, changes in pH can mediate theprotonation of histidine residues and hydrophobic sites, resultingin the disassembly of fibers in acidic environments (Fig. 9a).98

Recently, Stupp and Meijer et al. demonstrated that differentpreparation protocols can result in different morphologies. Experi-mentally, preparation pathways were changed by altering the orderof addition of water and HFIP, i.e. structure control by kinetics.However, the key parameters that were changed were the propertiesof solvents as well as the interactions between APs and solventmolecules.99 Moreover, by using MD simulations, Nguyen et al.investigated the kinetic mechanisms of AP assembly as a functionof the solvent conditions. The results revealed that increasing thehydrophobic strength, i.e. decreasing the hydrogen-bond-formingability of solvents, leads to structure transformation of aggregatesfrom open b-sheet networks, and nanofibers to elongated micelles(Fig. 9b).100 APs also form nanotube structures in water, as reviewedby Hamley;40 for example, through a slow kinetic time-evolutionprocess, the growth of AP nanotubes exhibits twisted tapes as wellas helical ribbons as intermediates.101 For another type of APs, thelipopeptide C16-KKFFVLK, NTs and twisted ribbons are achievedreversibly by manipulation of kinetic factors (e.g., temperature).102

Self-assembly of AP at interfaces

AP molecules can form spontaneously ordered structures, suchas monolayers at the interface. The understanding of thermo-dynamics and mechanisms of peptide organization at variousinterfaces, especially the hydrophobic/hydrophilic (e.g. air/water) interface, will provide valuable information in the bio-logical field, such as in studies of processes at cellular mem-branes. By MD simulations, Sayar and Hess et al. calculated thefree energy of adsorption of AP from bulk to the air/waterinterface. They found that there is a competition between thedehydration of hydrophobic side chains (driving force) and theloss of orientational degrees of freedom of AP molecules atthe air/water interface (opposing force).103 The presence of theair/water interface could help to distinguish the hydrophobic

and hydrophilic domains, resulting in stable peptide structures.104

Tanaka et al. have reported that the conformation of AP inAP-PEG conjugates showed an interesting transition from random-coils in aqueous solution to b-sheet structures at the solid/waterinterface.105,106

The design and control of peptide self-assembly at the inter-face can be achieved by several factors. For instance, Gellmanand Abbott et al. found that the sequence of AP molecules isimportant for generating ordered monolayers on gold.107 Gellmanand Rapaport et al. showed that the intramolecular backbonedipole–charge interactions of ionic side chains have a great impacton the assembly of a/b-peptides at the air/water interface.108,109

Moreover, the properties of the interface are also the key toadjusting the peptide assembly. For example, Nielsen et al. foundthat AP molecules show different conformations at the interfacewith different features. At the interface between water and a curvedcarbon-nanotube, AP molecules favored a strong a-helical confor-mation with its hydrophobic contacts with the nanotube and itshydrogen bonds with water.110

These ordered structures at interfaces also promise greatapplication potential in materials science. Rapaport et al. havereviewed the design and application of AP assemblies in mono-layers at interfaces.111 They also reported that acidic b-sheetpeptides exhibited compressibility and elasticity, which may beassociated with favorable cross-strand interactions between theside chains of peptides.112 Recently, Bai and Ulijn et al. success-fully utilized nanofibrous interfacial networks assembled byamphiphilic peptides through p-stacking and hydrogen bondinginteractions, to obtain a stable emulsion (Fig. 10).113,114

Polypeptides

Synthetic polypeptides (PP) are polymers composed of aminoacids. Investigating the PP assembly is helpful for understandingthe behavior of protein systems. The PP molecules have threetypical assembly conformations: random coil, a-helix, and b-sheet.Generally speaking, the conformation is connected with the

Fig. 9 Schematic diagram of the effect of (a) pH and (b) hydrophobic strength on the assembly of APs. Reproduced with permission from ref. 98 and100. Copyright 2014, American Chemical Society.


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solubility and rigidity of PP segments in solutions, and therandom coil structure is favored when the solubility is higher.Different factors, such as solvents, pH, and sequence, willinfluence the solubility and self-assembly of PPs.115,116 Valuableinformation on the important role and self-assembly behavior ofPP-based copolymers can be found in the reviews of Lin117 andDong,118 respectively.

On the other hand, as a perfect combination of flexiblepolymer and amino acids, the PP-based materials show diversenanostructures (including nanofibrils, lamellae) and various‘‘smart’’ properties.119 The structures of PPs can be kineticallycontrolled by environmental stimuli, including thermo-, redox-,pH, temperature, and photo-response. The application of thesestimuli-responsive PPs has been studied120–122 and reviewedrecently.123,124 Temperature is one of the most frequentlyused parameters because it can affect the hydrogen-bondingand hydrophobic interactions. These interactions affect thesecondary structures of PPs, for example, the structural transitionfrom a-helical (Fig. 11a) to random coil (Fig. 11b) due to alterationof the hydrogen-bonding, resulting in temperature-responsivebehavior.125 The thermo-treatment also drove the secondarystructure transition from helical to b-sheet, resulting in anassembly structure transition from micelles to nanoribbons.126

The secondary structures also play an important role in theformation of aerosols127 and thermo-gels.128 One example is that adecrease in the b-sheet content leads to a higher sol–gel transitiontemperature.129 Apart from temperature, other stimuli also impactthe secondary structure, e.g., an aggregation–dissolution transitionarising from the hydrophobic to hydrophilic switch and a decreasein the helical content under UV light.130 Moreover, Keeley et al.found that peptide concentration and ionic strength will influence

the hydrogen-bonding stability of water–PP and PP–PP, resulting inthe alteration of the kinetics of the coacervation and maturationsteps of the self-assembly.131

In addition, because of the easy regulation of the propertiesof PP segments, the PP-based copolymers can form functionalmicelles, vesicles, and brush layers on particle surfaces.132,133

For instance, He and Gu et al. utilized an end-functionalized

Fig. 10 (a) Cartoon of formation of fibrous network at the oil/water interface. (b) Fluorescence microscope image of emulsion droplets with ThT-labeled Fmoc-YL networks at the chloroform/water interface. (c) and (d) SEM micrographs of freeze-dried Fmoc-YL networks at the interface. The scalebars are 50 mm (b), 50 mm (c) and 2 mm (d). Reproduced with permission from ref. 113, Copyright 2014, American Chemical Society.

Fig. 11 Intermolecular hydrogen bonding illustration of (a) helical PP and(b) a random coil PP. Reproduced with permission from ref. 125, Copyright2013, Springer.


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linear PP cooperating with peptide dendrimers by electrostatic andhydrogen bond interactions to assemble virosome-like structures.134

Recently, Garanger, Chilkoti and Lecommandoux et al. obtainedtemperature-triggered micelles assembled by elastin-like PP, andthey found that the interactions between PP and water moleculesplay an important role in this thermally responsive process.135 Lealand Cheng et al. reported a photo-responsive PP vesicle formationwith a densely packed multilayer membrane. They found that theassembly of membrane structures can be determined by the size ofthe blocks in PP molecules (Fig. 12).136

Amyloid-relevant peptides

Amyloid fibrils are highly organized protein aggregates, whichhave a physiological role in microorganisms and in melanin-producing cells in mammals.137,138 Misfolding of uncontrolledprotein can lead to disorders, such as Alzheimer’s disease.139

The assembly kinetic models and thermodynamics of amyloidfibrils have been reviewed before by Wetzel,140 and Murphy.141

Different kinetic models of amyloid fibril formation, includingnucleated polymerization and monomer conversion, have beendetailed in their reviews. Therefore, we will not describe thesemodels again. The purpose of this section is to update studieson the thermodynamic properties and kinetic control ofamyloid-relevant peptide self-assembly.

Although a large number of studies have been involved inthe formation of amyloid, the mechanism of peptide aggregationstill remains largely unclear. Knowles’s group has started manystudies on the assembly mechanisms, kinetics, and thermo-dynamics of amyloid fibril formation. They utilized a surface-sensitive technique, quartz crystal microbalance measurements,

to determine the elongation rate of the fibrils. Then, in terms ofArrhenius plots, the thermodynamic parameters, including freeenergy, entropies, and enthalpies of activation, were obtained.The results showed that fibril formation is an enthalpy-unfavorable but entropy-favorable process, stemming from theunfavorable formation and breakage of weak interactionsbetween peptides and water molecules (Fig. 13).142 They alsofound that the major interaction contributing to the stability ofthe amyloid-like fibrils is the interbackbone hydrogen-bondingnetwork modulated by variable side-chain interactions.21 Thus,the hydrogen-bonding propensity of the constituent moleculescan efficiently mediate the internal dynamics of nanofibers, asstated by Stupp et al.143 Moreover, the interaction pattern ofhydrogen-bonding yields two different nanostructures, i.e. anti-parallel and parallel b-sheets. In the early 2000s, Yamada et al.reported a useful amyloid model by using tripeptides. Theyfound that these tripeptides can form amyloid-like fibers witha rich amount of parallel b-sheet structure, and the parallelstructure can be transformed to antiparallel, if another tripeptide isadded.144,145 Harris et al. suggested that the antiparallel pattern isgenerally more stable than the parallel pattern, because the anti-parallel pattern can weaken the electrostatic repulsion and formmore hydrogen bonds.146 However, the antiparallel pattern may notform for peptides with strong hydrophobic residues. In this case,hydrophobic packing is favorable to overcome the balance ofhydrogen bonding and electrostatic interactions. Eisenberg et al.demonstrated that stable forces of aggregation are provided byinteractions at the interface between the paired b-sheets consistingof the self-complementing hydrophobic side chains, the so-calledsteric zipper.147

The assembly kinetics of amyloid fibrils has always been anattractive topic. Knowles et al. worked out a set of coupled

Fig. 12 (a) Schematic illustration of photo-responsive PP vesicles with densely packed multilayer membrane and (b) the influence of blocks on theproperties of membrane structures. (c) Cryogenic TEM images of PEG1k-b-PL20 vesicle. (d) Small-angle X-ray scattering scans for five different assembliesof PEG-b-PL. Reproduced with permission from ref. 136, Copyright 2015, The Royal Society of Chemistry.


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kinetic equations by analytical treatment to reveal that thekinetics of amyloid growth is dominated by secondary ratherthan by primary nucleation events.148 By using IR and NMR,Mehta et al. found that, unlike Ostwald-like ripening, theassembly of Ab16–22 is related to a series of conformationaltransitions (Fig. 14).149 The kinetics of amyloid fibril formationcan be significantly influenced by many factors.150–154 Forexample, Goto et al. found that the presence of NaCl can not

only affect the final structures but also accelerate the aggrega-tion of amyloid.155 Gao et al. demonstrated that the dominantpathways and molecular mechanism of Ab37–42 aggregationwere different in pure water and salt solution by using all-atom MDsimulation.156 The peptide concentration can alter the intermediatespecies of Ab1–40 aggregation. Especially at high concentrations, thekinetics of fibrillation does not always follow traditional kineticmechanisms.157 Considering the influence of the peptide moleculeitself on the kinetics of assembly, C terminus and N-terminalsegments of peptide molecules may serve as ‘‘internal seed’’and ‘‘catalyst’’, respectively, for the assembly of Ab42 in water.158

Mechanical energy, such as ultrasonic treatment, shaking, andstirring, can influence the nucleation and growth kinetics offibrillation. Yokoi and Zhang proposed a sliding diffusion modelto explain the reassembly of ultrasonically damaged nanofibers(formed by a self-complementary 16-residue peptide).159 Infact, this reassembly may result from the ‘‘self-replication’’ ofbiomolecules. The mysterious ‘‘self-replication’’ ability is notonly essential to the origin of life, but also creates a chance toturn assembly from thermodynamic control to kinetic control.Otto et al. have reported fibrillation by mechanosensitivepeptide-derived disulfide macrocycles through autocatalyticself-replication.160

NTs are another type of important nanostructure formed byamyloid-relevant peptides. Studies on the amyloid peptide NTsare referred to in Hamley’s recent review.40

Concluding remarks and futureperspectives

Peptide self-assembly is an important and interdisciplinaryresearch field involving chemistry, materials science, and lifescience. Peptides can be utilized to prepare different architectures,including NTs, nanospheres, NWs, and nanofibers. These nano-structures present significant potential for applications in advancedmaterials, notably in green-life technology and biomedicine. Theformation of ordered structures and functional architectures is nota result of single intermolecular non-covalent interactions, but ofthe cooperation of various non-covalent interactions, includinghydrogen-bonding, p–p stacking, electrostatic, hydrophobic, andvan der Waals interactions. Their interplay gives rise to dynamicand responsive changes and allows for a multitude of structuresand morphologies. Although the self-assembly process is mainlydriven by thermodynamics, kinetics is a critical factor in structuralmodulation and function integration. However, the systematicunderstanding of the governing mechanisms and thermodynamicproperties of peptide self-assembly is important but still in itsinfancy.

Therefore, we have touched on and highlighted recent studieson the self-assembly thermodynamics and kinetics of the typicaltypes of peptide building blocks, such as aromatic dipeptides,amphiphilic peptides, polypeptides, and amyloid-relevant peptides.Typical examples of thermodynamic and kinetic studies are listedin Tables 1 and 2, respectively. The thermodynamics studies aremainly focused on two points: (1) governing/driving forces; and

Fig. 13 Overview of the values of activation parameters of different kindsof amyloid-relevant peptides. Reproduced with permission from ref. 142,Copyright 2012, Wiley.

Fig. 14 (a) Model for the progressive transitions observed for Ab16–22.TEM images of the time dependence of Ab16–22 assembly at (b) 1 h, and (c)20 days; scale bars are 200 nm. (d) Time dependence of isotope-edited IRanalysis for assemblies. (e) Determination of peptide registry with NMR.Reproduced with permission from ref. 149, Copyright 2014, AmericanChemical Society.


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(2) free energy of assembly. The kinetic studies also have twoimportant aspects: (1) structural regulation by kinetics; and (2)kinetic nucleation and growth processes. For example, for aro-matic dipeptides, emphasis is placed on the understanding ofdriving forces and structure control, while for the amyloidpeptides, the focus is on the thermodynamic energy and kineticgrowth process. In fact, there is in many cases no obviousboundary between thermodynamic and kinetic control. For example,

kinetic control through designing molecules or altering thesolvent properties is a disguised thermodynamic control inessence, because these kinetic controls disturb the balance ofthe original driving forces or change the energy barriers (Fig. 1),resulting in a kinetically trapped state. Another typical kineticcontrol is a way to influence the time scales of the key nuclea-tion steps in the assembly process. This method is alwayssuited to peptides that are easy to fibrillate, including amyloid

Table 1 Typical examples of thermodynamic studies of peptide self-assembly

Peptide sequence Nanostructures Dominant interactions/energy Ref.

Driving forcesFF NTs HPI, EI 37FF NTs HI 38— Gels HI, HPI 75–77FF NWs on surfaces HI 80FF NTs on surfaces HPI 81, and 82Branched AP Micelles, fibers EI 89A6K, V6K Coil, b-sheet HPI, HI, EI 92a-Lactalbumin Fibril HI 21GNNQQNY, GGVVIA Fibril HI, EI 146Ab1–40 Fibril HPI, EI 153

Driving energyBoc-FF NTs Gibbs free energy 39FF Fiber bundles Entropy (Onsager theory) 56Fmoc-FF (as model) Fibers Gibbs free energy 74Ace-(Val-Asn)n-NME Molecular layer Gibbs free energy 103PI3K-SH3 Fibril Entropy 142Ab1–40 Fibril Gibbs free energy 153GNNQQNY Fibril Gibbs free energy 154Ab1–42 Fibril Gibbs free energy 158

Note: the abbreviations HI, EI, and HPI represent hydrogen-bonding interactions, electrostatic interactions, and hydrophobic interactions,respectively. The dominant interactions in the third column do not mean that they are the sole interactions present in the system. Any assemblyprocess is actually the synergistic effect of various non-covalent interactions.

Table 2 Typical examples of kinetic studies of peptide self-assembly

Peptides Starting state Kinetic triggers Trigger-tuned structures Ref.

Structure regulationFF-based NT Solvent (pH, IS) NW, NS, fibers, NR 31, 34, 39, 42, 49, 51, and 52

NT Temperature Fibers 45, and 54NT Concentration NW, NS, fibers, NR 31, 34, 43, 47, and 51NT Interface Fibers 42, and 49NT Ultrasound NW 31Crystals Solvent (pH, IS) Fibers 23, 55, and 66Crystals Temperature Fibers 55Fibers Solvent (pH, IS) NB 67

AP-based Fibers Solvent (pH, IS) Coil, helix, ribbons 90, and 97–100NT Temperature Ribbons 102

PP-based — Temperature Coil, ribbons 125–127, and 129Micelle UV light Dissolution 130

Kinetic of nucleation, growth, and fibrillation processFF-based — — Fibrils 53AP-based — Solvent (pH, IS) Gel 71

Ribbons — NT 101PP-based — Solvent, temperature Coacervate 131Amyloid — Solvent (pH, IS) Fibrils 151–153, 155, and 156

— Temperature Fibrils 152, and 153— Concentration Fibrils 148, 152, 154, and 157— Ultrasound Fibrils 155, and 159

Others — Shaking, stirring Fibers 160

Note: the abbreviations NT, NW, NR, and NB represent nanotubes, nanowires, nanorods, and nanobelts, respectively. The abbreviation IS meansionic strength.


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and amphiphilic peptides with more hydrophobic residues.Notably, the new concept of ‘‘catassembly’’, i.e. the combinationof catalysis and assembly, is also a suitable way to increase therate of assembly.161

To sum up, much effort has been devoted to obtaining insightinto the thermodynamics and kinetics of peptide assembly. Infuture, this research field is expected to expand towards morecomplex structures and even to systems that are closer to biologicalones, not only in structure but also in functionality. For example,(i) peptides containing more informative motifs are highly appre-ciated for structural assembly and regulation by the complementaryinfluence of thermodynamics and kinetics,2,162–164 so that dynamicand/or multifunctional architectures, having more opportunitiesfor biomedical applications, can be obtained. (ii) Combiningpeptides and other functional biomolecules (such as porphyrins)enables self-assembly and structural diversity by the control ofthermodynamics and kinetics,35,41,56,165 so that more complexsystems, similar to biological functional assemblies, can be created.(iii) Structural complexity over different length scales will requireprecise control of the self-assembly process,166–169 not only sub-jected to one control path (thermodynamics or kinetics), but alsothe combined control of both thermodynamics and kinetics. Withthe precise and effective control of the self-assembly process ofpeptide-based structures, complex and multifunctional systems canbe expected. This may greatly push forward peptide self-assemblyand promote the development of peptide-based materials towardsreal-life applications.

Acknowledgements

We acknowledge financial support from the National NaturalScience Foundation of China (Project No. 21522307, 21473208and 91434103), the Talent Fund of the Recruitment Programof Global Youth Experts, the CAS visiting professorships forsenior international scientists (Project No. 2016VTA042) andthe Chinese Academy of Sciences (CAS). X. Y. is greatly indebtedto Prof. Mohwald for his long-term support.

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