Folding and replication in complex dynamic molecular networks
Liu, Bin
DOI:
10.33612/diss.99784510
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Publication date: 2019
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Liu, B. (2019). Folding and replication in complex dynamic molecular networks. University of Groningen. https://doi.org/10.33612/diss.99784510
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Chapter 1 Folding and Replication in Complex
Chemical Systems
The origin of life and the de novo synthesis of life are among the greatest challenges in contemporary science. It is well known that life consists of many complex processes in which self‐replication and folding play key roles. One of the most important features of a living system is its ability to replicate itself. Self‐replication is one of the most important ingredients in the origin of life and self‐replicating molecules are a promising starting point for the de novo synthesis of life. Folding is the process by which proteins and nucleic acid strands acquire a three‐dimensional structure with a biologically functional conformation in a fast and reproducible manner. The most critical metabolic processes in organisms rely on the correct folding of biomolecules such as proteins and DNA. Therefore, the study of self‐replication and folding may not only help us uncover the mystery of the origin of life, but may also guide us to synthesize life.
Dynamic combinatorial chemistry (DCC) is a promising tool for creating and studying chemical complexity. DCC not only allows us to simulate and control the process of self‐replication, but also to study the process of folding. More importantly, as demonstrated in this thesis, DCC provides a simple way to combine these two complex processes in a single system. In this chapter, we first briefly highlight the current state of the art of synthetic folding and self‐replicating systems, and then we summarize the folding and self‐replicating systems constructed by using DCC. Finally, the contents of this thesis are outlined.
The central principle of molecular biology includes two important parts: the replication of genetic information and its transcription into proteins. Replication of genetic information is a biological process that occurs in all organisms and is the basis of biological inheritance. Proteins, as the basic substances of cells, play an important role in all living systems. In order to achieve functions, the protein needs to be correctly folded into a three‐dimensional structure. The synthesis of proteins in the cell starts with messenger RNA which is formed through the transcription of DNA, which is then translated into unfolded or randomly coiled peptide chain. Finally, the linear peptide chain is folded into a three‐dimensional structure borne from the primary sequence. The primary sequence of a protein plays a decisive role in its folding, but environmental changes and chaperones may also affect the spatial structure of the protein (secondary, tertiary and quaternary structures) and biological activity. In the majority of the protein structures hydrophobic residues are concealed inside the protein, minimally exposed to the solution, and hydrophilic residues are exposed to the outside and interact with the solution to stabilize the protein conformation.
1.1 Systems chemistry and the de‐novo synthesis of life
For many years, chemists have been more inclined to study isolated substances than complex mixtures of molecules that can interact and react with each other. Nowadays, this situation is likely to change because of the great interest in systems biology and the availability of analytical techniques.1,2 Unlike other areas of chemistry that focus on simple systems, systems chemistry tends to study multiple variables simultaneously. Over the past decade, scientists have established three thermodynamic models for characterizing complex chemical systems: (i) systems that achieve minimum energy states under thermodynamic control, and (ii) systems that can be trapped in local minimum energy states under kinetics control, and (iii) systems that are kept away from equilibrium by continuous energy input.3‐5
The emergence of systems chemistry has spurred effects directed towards the de‐novo synthesis of life and the origin of life. A reasonable approach toward constructing the first protocell, from the highly diverse components available on prebiotic Earth, involves the integration of primitive metabolism, self‐replication and membrane subsystems through different physicochemical mechanisms and reaction pathways.6 The prebiotic Earth can be seen as a huge reactor that contains complex, different types of small molecules that engage in a huge variety of possible interactions and reactions. When such systems are maintained far from equilibrium, this complex collection can explore an extremely large number of possible reaction pathways. Attempts at identifying thermodynamically sound chemical pathways leading to life often involves studying a mixture of
potential molecular components and studying the chemical and physical interactions between them (eg, interconversion, condensation, and polymerization).
DNA and proteins are two of the most important molecules in all known living systems. However, the DNA‐protein tandem seems too complicated to appear spontaneously. There is a “chicken and egg” problem: which is first, chicken (protein, phenotype) or egg (DNA, genotype)? The most widely accepted solution to this problem is the existence of an RNA world before DNA and proteins.7 RNA is ubiquitous and plays a different role in nature: in addition to storing genetic information, it is also involved in gene expression, catalysis and translation of some steps in the flow of genetic information. The chemical basis of this versatility relies on the fact that RNA is usually a single‐ stranded molecule, thus facilitating intramolecular base pairing to generate more types of three‐ dimensional structure/functional motifs than double‐stranded DNA. The secondary structure of RNA also provides a simplified and appropriate phenotype of the genotype, which is useful for solving related evolutionary problems. Therefore, the clear relationship between sequence, structure and function makes RNA the best model for molecular evolution experiments and computational studies. Although the possibilities of the RNA world are supported by some experiments, a "spontaneously generated" RNA world that produces proteins and DNA is not obvious. Perhaps more importantly, the initial emergence of the RNA world itself remains an open question.
Self‐replication can be considered as a key process for a protocell. Autocatalysis is a relatively rare and complex behavior in chemistry.8 In addition, autocatalysis is also the basis for oscillatory behavior in several reactions. Autocatalysis is a fundamental concept for all living systems that make more copies of themselves, and it produces a series of potentially more complex systems through evolution. Without autocatalysis, the transition from a chemical system to a biological system does not seem to be feasible. Furthermore, the process of self‐replication makes information transfer between molecules and systems possible, which is essential for Darwinian evolution.
Metabolism is another important ingredient.9 The metabolic network in life is a large chemical reaction system with amazing complexity and adaptability.10 It has two main purposes: the first is to convert energy in the environment into a form of energy that is useful to the organism; the second is to obtain nutrients from the environment to synthesize the small molecules needed for cell growth. These small molecules include DNA nucleotides, RNA nucleotides, sugars, lipids and amino acids. Most reactions in an organism are controlled by enzymes, which determine the rates and the selectivities. An enzyme must be folded into a specific configuration before it can perform its function.11 So the process of folding is the key to bring functions to biomolecules.
As part processe establish (1.2 and
1.2 Syn
The wor polymer added o state in between explorat Accordin classified highlight 1.2.1 Ali Folded p 20 natur foldame Strategie chains o effective the most of building es of self‐re hed separate1.3) we will
nthetic fold
d ‘foldamer’ r with a stro on this definsolution, th n non‐adjace tion, chemist
ng to the dif d into two cl t the most im phatic pepti peptides are ral amino ac rs can also a es for the m or the peptid e and involve t popular ali a synthetic plication (ge e systems th briefly summ
ded struct
’ was used fo ong tendenc ition as "A f e structures ent monome ts have succe fferent back lasses: alipha mportant ach ide foldame the structur ids are arran adopt well‐d modification o de backbone es introducti phatic peptid Figure 1. protocell, w enotypes) an hat show eit marize synthures ‐ fold
or the first ti cy to adopt foldamer is a of which ar er units".14 essfully synth bones of th atic peptides hievements f rs ral basis for p nged dictates defined confo of folded str s. Modifying on of non‐n des foldame .1. The backbowe must fin nd folding (p ther folding hetic folding
damers
me in 1996 b a specific c any oligome re stabilized In recent ye hesized vario e synthetic s and aroma for synthetic proteins to a s dynamicity ormations.16 ructures hav g the backbo atural peptid ers.18 ones of alipha d a reasona phenotypes) or self‐repli and replicat by Gellman. compact con er that folds by a collect ears, after c ous helical st folded struc atic foldamer c foldamers. achieve their y and the fun 6 In most cas ve focused o one of peptid des. Figure 1 atic peptides fable way to . In past stu cation. In th ing systems.
He proposed nformation".
into a confo tion of non‐c continuous e tructures and ctures, folda rs.15 In this s r functions. T nctional shap ses these are n modifying des has prov 1.1 summariz foldamers combine th udies, scient he following d the definit .12,13 In 2001 ormationally covalent int experimenta d functional mers can be section we w The way in w pe. Synthetic e helical stru g the amino‐ ven to be pa zes the back hese two ists have sections ion: "Any 1, Moore y ordered eractions ation and folds.15 e roughly will briefly which the c peptide uctures.17 ‐acid side articularly kbones of
β‐Peptid foldame hydroge peptides atoms ap Analogo bonding shows th bind to α Kunvar u an order de foldamers r consisting n bonds bet s that adopt part (Figure Figu us γ‐peptide between ad hat it is folde α and γ posi used carbofu red 9‐helix st Figur s are determ g of cyclic β tween sites t a 14‐helix 1.2b).21 re 1.2. The β‐ e foldamers djacent amid ed into a C9‐ tions of prol uranosyl as a tructure (Fig re 1.3. C9 H‐b mined by 12 β amino‐acid separated b with intram ‐peptide (a) 12 s are more de bonds.23 T ‐related stru line are in th a conformati ure 1.3b).25 bonded rings i and 14 hel ds to form by 12 atoms molecular hy 2 and (b) 14 h likely to ac The NMR of ucture. In the he same plan ional stabiliz n γ‐peptide fo ices.19 Gellm a stable 12 s (Figure 1.2 ydrogen bon helical folds. A quire confo the cis‐γ‐am e secondary ne as the pro zing side cha oldamers. Ada
man et al. co 2‐helical con 2a).20 Seebac ds between Adapted from rmational st mino‐1‐prolin structure, tw oline (Figure in to force t apted from re onstructed a nformation ch et al. des
amides tha ref.22 tability by h ne γ‐peptide wo amide bo e 1.3a).24 Sha the γ‐peptide ef.24,25 a peptide featuring signed β‐ at are 14 hydrogen in water onds that arma and e to form
1.2.2 Aro The field rings we to the ro of an or 1.4a).26 benzene hindranc five ben benzene to obtai member combina form a b oligome extende Figure Apart fr common omatic folda d of aromati ere connecte otatability of rtho‐benzene Yashima et e ring, giving ce limits its c zene rings, e, six‐membe n biphenyl‐l red heterocy ations thereo biphenyl‐like rs constructe d to form a h 1.4. Molecula om direct b n methods fo amers ic foldamers ed directly to f the C‐C bon e subunit re al. synthes g rise to an
conformatio which can f ered aromat ike molecule ycles such a of can also fo e structure w ed by Moore helical config ar structures w bonding, the or obtaining s started wit o each other. nd. Simpkins esulting in a ized anothe angle of 120 nal freedom orm a doub ic heterocyc es, folding in as thiophene orm differen when they c e can not onl guration (Fig with different fr
use of ami g aromatic fo
th the synth . These mole s et al. synth
n angle of 6 er type of b
0° between m, leading to ble helix in w
lic rings such nto various s e, furan, tri nt helical stru connect two ly form a cyc gure 1.4e).39,4 t aromatic ring rom ref.26‐28,34
des to link oldamers.41 T
esis of a he ecules can ad esized a biph 60° between biphenyl stru adjacent aro the formatio water.27 Due h as pyridine structures (F azole and o uctures (Figu benzene rin clic six‐memb 40 gs folded into 4,39 different aro The amide b lical structur dopt differen henyl oligom n adjacent b ucture using omatic rings on of a helic to the stru e derivatives Figure 1.4c).2 other conjug ure 1.4d).34‐38 ngs. The m‐ bered ring bu o different hel omatic units bond has a p
re in which nt conformat mer by direct benzene ring g a meta‐su s (Figure 1.4 cal structure ctural simila can also be 28‐33 In addit gated struct 8 Acetylene phenylene a ut can also b ical shapes. A
s is one of t planar rigid aromatic tions due t bonding gs (Figure bstituted b). Steric of about arity with included tion, five‐ ures and units can acetylene be further Adapted the most structure
and is al and can rotation, conform using am A series the pion amide fo by hydro forming 1.5b).48,4 replacing In the de are wide Lehn rep oligome showed stranded quinolin tricentric rings suc building different so a good hy form a hyd , which faci mation. Recen mide bonds.4 of hydrogen neering work oldamer, wh ogen bonds ( folded stru 49
In additio g the amide Figure esign and pr ely used to c ported a pyr ric molecule that the he d helix in so e could gene c hydrogen ch as derivat blocks to co t types of h ydrogen bon rogen bond litates the i ntly, rapid p 2‐46 n‐bonding‐dr k of Gellman ich consists (Figure 1.5a) uctures using n, the same bonds with 1.5. Non‐hete reparation o control the c ridine‐based es with helic elical oligom olution. In a erate oligom bond (Figur tives of pyrid onstruct var helical oligom nd donor and with a neigh nteraction b progress has riven non‐he n on peptid of an amide .47
After tha g a methoxy research gr hydrazide bo erocyclic arom of amide‐bas onformation amide folda cal conforma mer exhibited subsequent mers that pos e 1.6b).55 Ap dine and qui ious helical mers by usin
d acceptor. It hboring hyd between aro s been made eterocyclic ar e‐based fold ‐linked benz at, Li and Zen y group at roup synthes onds (Figure matic amide fo sed aromatic n of the fold amer in 200 ations const d a dynamic t study, they ssessed a co part from th inoline, naph structures ( ng quinoline t can be intr rogen bond omatic rings e in constru
romatic amid damers. Gon zene ring tha ng et al. prep the 2‐positi sized novel a 1.5c).50,51 oldamers. Ada c foldamers, amers throu 00 (Figure 1.6 tructed by p c exchange y found that
mpact folde he pyridine hthalene and Figure 1.6c, e derivatives oduced into donor or ac and the ad cting aroma de foldamers ng's group re at forms a fo ared similar on of the b aromatic hyd apted from re aromatic he ugh hydrogen 6a). They sy yridine amid between a t the δ‐amin d conformat and quinolin d anthracene d and e). H ,56 hydrazine the aromat cceptor to li doption of a atic folded s s were repor eported an lded structu oligomers c benzene ring drazide folda ef.47,48,50 eterocyclic m n bonds.52‐54 ynthesized a de units. Th single and no acid deriv
tion through ne, other co e can also be
uc et al. con e derivatives ic system mit bond a specific tructures rted after aromatic re driven apable of g (Figure amers by molecules 4 Huc and series of he results a double ved from h a stable onjugated e used as nstructed s57,58 and
their hy phenant 1.2.3 Ali The hybr of both t first such a rigid herringb structure Waals in
1.3 Syn
Understa consiste During t ybrids.42,59 C throline and Figure phatic and a rids of arom the aromatic h hybrid that helical stru bone spiral.66 e is formed nteractions onthetic self
anding the e nt with living he past twohen et al. ortho‐benze e 1.6. Heteroc aromatic hyb atic and alip c and the alip t folded in an ucture, whic 6 For molecu by π‐π intera or hydrogen b
f‐replicati
essence of th g systems re o decades, a constructed ene rings.60 cyclic aromati brid foldame hatic buildin phatic folded n aqueous en ch, upon fin ules with alte action betwe bonds betweng system
he process o quires the d large numba new clas
ic amide folda ers ng blocks hav d structures. nvironment. ne‐tuning g ernating aro een adjacent een adjacent
ms
of self‐replica evelopment er of such s ss of helica amers. Adapte ve the poten 62‐64 In 1995, 65 Huc et al. ives rise to omatic and a t or non‐adja t or non‐adja ation and es t of minimal elf‐replicatin l oligomers ed from ref.55‐ tial to posse , Lokey and I introduced a o a new he liphatic unit acent aroma acent aliphat stablishing se synthetic sel ng systems h using hete ‐57,60,61 ess the chara verson desc a methylene elical struct ts, the intram atic rings and tic units.67‐69 elf‐replicatio lf‐replicating have been d erozygous acteristics ribed the e group in ture—the molecular d van der on theory g systems. evelopedfrom sim we will s systems molecule In gene autocata catalytic the self‐ formed autocata to be co The first of which complem speed u channel by molec noncova mple self‐rep summarize t based on es.
eral, a mol alytic proces cally active t replicators m during the alysis. Figure nsidered. channel is t h is the tem mentary bina p the initial is autocataly cular recogn alent dimer o plicators ope he most sign biological m ecular self‐ ss. The rate template. Se must form sp early stage e 1.7 shows a Figure 1.7. M he non‐cata mplate T of t ary complex l reaction ra ytic. In this c nition to form of the produ rating in isol nificant deve molecules, i ‐replicating of the auto elf‐replicating pontaneously es of the re a minimal rep
Minimal mode
lytic bimolec the self‐repli [AB], which ate, the resu channel, first m a catalytic uct [T‐T]. Its lation to com elopments an including DN system tra ocatalytic re g systems u y at the beg eaction cata plicating sys el of self‐replic cular reactio icating syste has no activ ulting templ t, starting m ternary com dissociation mplex replica nd achievem NA, RNA an nsfers struc eaction is di sually featu inning of the alyzes the s tem, in whic cation. Adapte n between c em. In the s ve recognitio late is cataly
aterials A an mplex [A‐B‐T] produces tw ator network ents for synt nd peptides ctural infor rectly relate re two react e reaction. S ynthesis of ch several rea ed from ref.74 components econd chann on site. Altho ytically inert nd B are bou ]. Then A and wo separate ks.70‐73 In this thetic self‐re s and small rmation thr ed to the am
tion process Secondly, the copies of action chann 4 A and B, the nel, the pro ough this cha t. The third und to the te d B react to template m s section, eplicating l organic ough an mount of ses. First, e product itself via nels need e product duct is a annel can reaction emplate T form the molecules,
each of which can participate in another replication cycle. In an ideal self‐replication system, the number of templates in the system is doubled in each cycle, so their growth is exponential. However, as components A and B are depleted, the growth rate diminishes and eventually stops. Overall this leads to the sigmoidal growth curve, typical of autocatalytic reactions in closed systems.
1.3.1 DNA‐based self‐replicating systems
In 1986, Günter von Kiedrowski developed the first non‐enzymatic chemical self‐replicating system based on an oligonucleotide strand with a palindromic sequence (Figure 1.8).75 In the replication cycle, a trinucleotide CCG (protected at the 5’ end) was coupled with another trinucleotide CGG (protected at the 3’ end) in the presence of EDC to generate a template hexanucleotide CCGCGG. The resulting 5' and 3' protected hexanucleotide CCGCGG facilitated the formation of a reaction product that was both complementary and identical to the template via Watson‐Crick base pairing. The resulting double‐stranded product can then dissociate into two single‐stranded molecules that can be used as templates for next catalytic cycle.
Figure 1.8. The first chemical self‐replicating system reported by von Kiedrowski in 1986.
The existence of an autocatalytic pathway in this system was demonstrated by the addition of a small amount of template at the beginning of the reaction which was found to accelerate product formation. However, the uncatalyzed background reaction contributed significantly to the overall reaction rate. Another limitation of this system is that the reaction rate is slow and only 12 % product formed after 4 days reaction.
In a subsequent experiment, von Kiedrowski and colleagues found that the problem of low efficiency can be solved by replacing the phosphodiester bond in the DNA strand with a phosphoramidate
linkage.76 Furthermore, the rate of self‐replication relative to the background reaction was increased in this system, and they therefore observed the first synthetic self‐replicator with a sigmoidal growth profile. However, the growth of the replicator was parabolic rather than exponential. After that, they found that this approach can also be applied to a self‐replicating system consisting of three nucleotide building blocks.77 Zielinski and Orgel also established a self‐replicating system based on 3’‐ amino‐3’‐deoxynucleotides. However, the replication of the resulting tetranucleotide was, again, hampered by product inhibition.78
To obtain a self‐replicating system with exponential growth properties, von Kiedrowski and colleagues designed a method called SPREAD (surface‐promoted replication and exponential amplification of DNA analogs).79 In their method, the single‐stranded template was first immobilized onto the surface of a solid support and then the complementary nucleotide fragments were bound to the template. The nucleotide fragments were linked by a coupling reagent and the product was then liberated from the template at elevated temperature to free the template and product for a second replication cycle. The liberated product was bound to free sites on the surface of the solid support and the above process was repeated to obtain exponential growth.
1.3.2 RNA‐based self‐replicating systems
Paul and Joyce successfully developed the first RNA‐based self‐replicating system in 2002 (Figure 1.9).80 Their experiments employed a modified R3C ligase that catalyzes the formation of 3',5'‐ phosphodiester bonds between two separate RNA molecules. The RNA ribozyme template T is capable of achieving its own precise replication by ligating two RNA subunits A and B through a ternary complex. The addition of a pre‐formed template to the reaction revealed a significant increase in the initial rate of template formation, indicating that template formation was an autocatalytic process. However, the increase in reaction rate occurs only in the initial stage of the reaction, which indicates that product self‐inhibition occurs. Kinetic fitting revealed that the reaction contained two phases. The increase in replication rate observed early in the reaction is attributed to the formation of the [A_B_T] complex. In contrast, the second, slower phase is the bimolecular reaction of A and B without a template. The authors suggested that the inefficiency of the designed RNA system is due to the similarity in the nucleotide sequences of components A and B, which leads to the formation of the inactive binary complex [A_B], which does not dissociate even upon addition of the template. Subsequently, they found that the deleterious effects on the replication due to the formation of the stable complex [A_B] can be avoided by premixing T with B before adding A or by adding an excess of A to the reaction mixture.
They hav were ca but the subsequ the synt These cr other bi modifica 1.3.3 Pe Ghadiri e simple p assembl interacti capable the stab heptad r replicatio two pep template occurred Kinetic e ve further m pable of cat new self‐re ent work, th hesis of eac ross‐replicati iological ma ations to get ptide‐based et al. report protein consi ed into two ions (Figure of driving th bility and hel
repeats drive on of the pe ptide buildin
e are assem d to produc experiments Figure 1.9. R modified the talyzing each plicating sys hey develop h other from ing RNA enz aterials and further insig self‐replicat ed the first isting of a se o entangled 1.10). Amin he recognitio ical orientat e intramolec eptides relie g blocks con mbled into a e a stable a showed tha
NA based self
structure of h other’s syn stem still ex
ed two mut m a mixture o zymes under can persist ght into the R ting systems peptide‐base even‐peptide coiled‐coil s no‐acid resid on between tion of the c cular recogni es on native ntaining a th a ternary co amide bond t the additio f‐replicating sy f the ligases nthesis.81 Th xhibited ‘bur tually replica of four diffe rgo sustained t indefinitely RNA‐based s s ed self‐replic e repeat (ab structures a dues at posi the helices coiled‐coil st ition by elec chemical lig hiobenzyl es omplex with by intramo on of templa ystem. Adapt in order to his modificat rst phase’ ki ative RNA en erent structu d amplificati y. In additio self‐replicatio
cating system cdefg)n cont
s a result o tions a and
by hydroph ructure. Res ctrostatic int gation. Unde ster and free h a coiled‐c olecular rear te at the beg ed from ref.80 generate tw ion resulted netics simila nzyme syste ral units by on in the ab on, they als on mechanis m in 1996.90 aining 32 re of hydropho d of the pe hobic interac idues at pos eractions. Th er the direct
e cysteine, r coil structure rrangement ginning of th 0 wo RNA enzy d in cross‐re ar to earlier
ms that can template gu bsence of pr so made a sm.83‐89
0 Their system
esidues, whic bic and elec eptide sequ ctions and d sitions e and he realizatio tion of the t respectively, e. Then the at the junct he reaction p ymes that plication, ones. In catalyze uidance.82 oteins or series of m used a ch can be ctrostatic ence are etermine d g in the n of self‐ template, and the e ligation tion site. promoted
the form Howeve process dissociat Subsequ Although the stab structure partially the inco addition double‐s system c nanoshe facilitate exponen diminish 1.3.4. No In 1990, organic mation of pr r, due to th shows parab tion of the d Fi uently, Chmi h the system ility of the d e by subtly solved the p orporation of of proline stranded he consisting of eet‐like struc
e the replic ntially. Howe hes. on‐biologica , Rebek and molecules.95 oduct, show he high sta bolic growth ouble strand gure 1.10. Pe ielewski and m exhibited a duplex. To so modifying t problem and f proline int makes the elix structure f alternating ctures in w cation react ever, upon ag al self‐replica colleagues 5 This syste
wing the abil bility of the . This is the ds previously ptide based s d colleagues sigmoidal g olve this prob the sequenc d resulted in
to the peptid peptide seq e.93 Ashkena
hydrophobic water.94 The
tion. A kin ging, the asse
ating system developed t m utilizes t
lity of the d e double‐str same proble y observed in elf‐replicating s developed rowth curve blem, Chmie ce of the te close to exp de sequence quence more asy et al. c c and hydrop
assembled etic analysi embly morp
ms
the first self the amide b esigned coil randed coile em as the in n nucleic acid g system. Ada a similar p e, the replicat elewski reduc emplate pep ponential gro e can achiev e distorted a constructed philic amino nanostructu is shows th hology chan f‐replicating bond format ed‐coil pept ed‐coil struct hibition of s d‐based self‐ pted from ref peptide self‐ tion process ced the stab ptide.92 This owth. In addi ve the same and reduces a β‐sheet‐b acids that ca ures can ac hat the sys ges and the
system base tion betwee
tide to self‐r ture, the re self‐replicatio ‐replicating s f.70 ‐replicating s s was still inh ility of the c simple mod ition, they fo e effect, bec s the stabilit based self‐re an be assem ct as a tem stem initiall replication e
ed on fully en an amine
replicate. eplication on by the systems. system.91 hibited by oiled‐coil dification ound that cause the ty of the eplicating bled into mplate to ly grows efficiency synthetic e and an
activated no sigmo amount process. catalyzed the Rebe analysis pathway reaction catalytic (pathwa the leng complex replicatio In 1997, reaction were co reaction studying effects.1 developm research d ester as a s oidal growth of amide te However, in d by the add ek system.96 of the Rebe ys that prom
pathways d c pathway is y II). Subseq gth of the xes, and final on systems b Fig , Sutherland between m nfirmed by t to construc g the effects 07‐112 In add ment of a se h found that strategy for f h curve was emplate to n 1994, Men dition of a sim This controv k system.97 C mote the fo depends on s the prima uently, Rebe self‐replicat lly observed based on mo gure 1.11. Non 's group rep aleimide and the addition ct two struc of structura dition to util
elf‐replicatin the constru forming tem observed, t the reaction nger and his mple amide, versy was fin Complete kin rmation of the concen ary pathway ek and collea ting precurs the S‐shape olecular reco n‐biological se
ported a non d cyclohexad of a pre‐for cturally simil al variation o izing the Di g system ba ction of effic mplate 3 from the initial re n mixture, c s colleagues which cause nally resolved netic analysi the final pr ntration of t y for produc agues redesig sors misma ed growth cu ognition in lat elf‐replicating n‐biological diene.106 The rmed templa ar furan and on replicatio iels‐Alder re sed on the 1 cient self‐rep m adenine de action rate w confirming th found that t ed doubts ab d by Reinhou s shows that roduct, and the reactant ct formation gned a new tched, hind urve.98 They a ter studies.99 g systems. Ada self‐replicat e self‐replicat ate. Philp and d maleimide on efficiency eaction, Philp 1,3‐dipolar c plicating syst erivative 2 (F was increase he existence the formatio bout the self‐ udt et al. thr t there are fi the contrib t. The binary n in this se self‐replicati ering the f also develop 9‐105 apted from re ing system b tion characte d colleagues e‐based repl and other r p and collea ycloaddition tems require igure 1.11). ed by addin e of an auto on of templa f‐replicating rough detaile
ive different ution of the y complex m elf‐replicating ing template formation o ped other sim ef.70 based on Di eristics of th s used the Di icating platf recognition‐m agues pione n reaction.113 es a certain d Although g a small ocatalytic ate 3 was nature of ed kinetic t reaction e various mediated g system e to make of binary milar self‐ iels‐Alder he system iels‐Alder forms for mediated ered the 3‐115 Their degree of
rigidity of the components and a suitable spatial arrangement of recognition sites to form catalytically active ternary complexes.116
1.4 Dynamic combinatorial chemistry
In the previous sections, we briefly summarized the state of the art in the fields of foldamers and self‐replicating systems. Although great achievements have been made in these fields, most of the systems developed relied on multi‐step organic synthesis and elaborate design. In addition, no connections have been developed between these two fields. Dynamic combinatorial chemistry not only enables the processes of folding and self‐replication to occur with a relaxed demand for multi‐ step synthesis, but also offers the possibility of linking and merging these two processes, as will be shown in this thesis.
The concepts and principles of dynamic combinatorial chemistry (DCC) were pioneered by Sanders and Lehn in the mid‐1990s.117‐120 DCC relies on a reversible process to spontaneously produce many possible combinations of a set of building blocks. Using a reversible reaction to form a dynamic combinatorial library (DCL), all components in the library can continuously interconvert by exchanging building blocks with each other.
The most commonly used reversible covalent bonds for constructing DCLs are imines, hydrazones and disulfides. Disulfide bonds play an important role in life’s chemistry.121 Proteins contain disulfide bonds, and thiols and disulfides maintain the redox state of cells. Disulfide bonds have the following characteristics:122 (1) In solution, thiols are easily oxidized to disulfides by oxygen in the air (Figure 1.12a). (2) The exchange of disulfide bonds can occur in the presence of a catalytic amount of thiolate anion (Figure 1.12b).
(3) The disulfide formation and exchange reactions are typically carried out under neutral‐weakly basic conditions and slow down under acidic conditions.
(4) The oxidation and exchange reactions can be carried out in aqueous solution, including under physiological conditions.
(5) The oxidation and exchange reactions can be carried out at room temperature with quantitative conversion.
The app molecule developm 1.4.1 Fol Balasubr formatio which co The resu homodim disulfide also bee different coil asse sequenc Gly‐Gly‐G dimer by heterodi Figur In additi of G‐qua Figure 1 plications of es and (c) se ments and a lding in DCLs ramanian’s g on of second onsisted of L ults show th mers of the l e exchange w en applied to t peptides th emblies.125 B ces were rep Gly linker at y oxidizing t imers were t re 1.13. Self‐s on, Balasubr adruplexes.12 1.12. Mechan DCC include election of f chievements s group found dary structur eu‐Lys repea hat self‐reco long‐chain se was enabled o tertiary str hat can form oth peptide placed with h one end, fo he cysteine transferred i orting of α‐he ramanian’s g 26 They chos ism for the fo
e: (a) select foldamers.117 s for self‐ass d that foldin re.123 They u at sequences ognition did equence, dir by using a re ucture‐direc m α‐helices, w s contain th hexafluorole llowed by a thiol group nto homodim elical peptide group also re e PNA in the ormation (a) a
tion of a ho
7 In this sect
sembly direct g can lead t sed two pep s of different not occur rected by the edox buffer cted peptide which are d e same sequ eucine residu cysteine res to a disulfid mer in redox assemblies by eported dyn eir research, nd exchange
ost or guest; tion, we will ted self‐repl to self‐sortin ptide buildin t lengths and upon fast o e formation based on glu self‐sorting esigned to f uence, excep ues. Each pe sidue, allowin e bond (Figu x buffer. y folding in re amic self‐ass , because PN (b) of disulfide ; (b) selectio l summarize ication and f ng of peptid ng blocks tha d featured a oxidation of of β‐sheets, utathione. Th .124 Kumar e orm parallel pt that all le ptide is equ ng for the fo ure 1.13). Th dox buffer. Ad semblies bas NA has good e bonds.
on of self‐re e the most s
folding by us de assemblie at can form cysteine at t the DCLs. H were obtain he same stra et al. synthes l homodime eucines in on uipped with ormation of a he author fo dapted from r sed on the fo water solub eplicating ignificant sing DCC.
es by the β‐sheets, the ends. However, ned when ategy has sized two ric coiled ne of the a flexible a peptide ound that ref.125 ormation bility, and
is easily functionalized with amino acids to introduce thiol groups for the exchange reaction. Under kinetic control, dimers TSST, GSST and GSSG are formed in approximately statistical ratio. In contrast, self‐sorting was observed under thermodynamic control in the presence of potassium ions, which stabilize the G‐quadraplex structure.
Inspired by folding directed self‐assembly of biomolecules, chemists have also developed folding‐ induced dynamic assemblies of synthetic systems. Moore's group developed a series of methods for assembling monomers into folded dimers and oligomers using reversible chemical bonds.127‐130 In most of their studies, they used imine metathesis catalyzed by oxalic acid in organic solvents. In their initial study, they used a mono‐functionalized building block to study the effect of oligomer length on the folding characteristics.127 They synthesized two types of m‐phenylene‐acetylene‐based building blocks with different lengths, one of which was functionalized by an amino group and the other by an aldehyde group, each capped by an imine (Figure 1.14). Simulations show that six aromatic units are necessary to form a complete helix, while additional aromatic units stabilize this folded structure. Indeed, the results of NMR studies indicate that imines containing two or five aromatic units didn’t form a helical structure, whereas stable helical structures were observed when the oligomers have more than six aromatic units. Folding caused the equilibrium of the reaction to be shifted towards the formation of longer oligomers that can form stable helical structures. Furthermore, the experimental results showed that no helix formed in chloroform, while a helical structure was observed in the more polar acetonitrile. In addition, they also found that the position of the imine bond in the helix did not significantly affect the stability of the helical structure, confirming that the imine is a suitable structural analog of the alkyne linker. Also, if the length of the building block is extended such that it forms a stable helix by itself, further increasing the chain length does not affect the position of the imine equilibrium.
The aut building only con the two assembly the leng because 1.4.2 Em Philp's g The DCL an amid benzalde equilibri At the e produce the proc accelera Fig hors also st blocks with ntained two building blo y. Folding‐di gth of the m spiral forma mergence of s group report Ls they studie de pyridine ehyde, a p‐f um, two imi nd of the re d, and this p cess was co te the rate o gure 1.14. Fol tudied foldin h two blocke aromatic un ocks were fo irected poly monomer. A ation is more self‐replicat ed the first ed contained unit with fluoroaniline ines and two eaction, it wa product was onfirmed by of the reactio ding‐driven sy ng‐directed ed amine or nits, no polym ormed, whic merization d As expected, e advantageo ors from DC self‐replicati d four differe recognition e and fluoro
o nitrones w as found tha s found to ha the additio on.132‐134 ynthesis of ol polymerizat aldehyde fu mer formatio ch were stac did occur up the polyme ous in polar s CLs ing system in ent compon n function ohydroxylam were formed. at only one o ave autocata n of a smal
igomers. Adap
ion.128 They unctional gro on was obse cked on eac pon changing er length in solvents. n a dynamic ents: two ald while the ine (Figure Then a mal of the four p alytic proper ll amount o pted from ref. used two m oups. When erved, but cy h other and g the polarit creases with combinator dehydes, one other aldeh 1.15). After eimide is ad possible prod rties. The au f template w f.127 m‐phenylene both buildin yclic dimers d formed a c
ty of the sol h increasing rial library in e of which c hyde was a r the library dded to the r ducts was se utocatalytic n which was e‐ethynyl ng blocks based on columnar vent and g polarity n 2008.131 contained a simple reached reservoir. electively nature of found to
Figure 1.15. 1,3‐dipolar cycloaddition triggered autocatalytic amplification from DCLs. Adapted from ref.70
Subsequently, Giuseppone’s group developed an autocatalytic system using imine‐based DCLs in 2009.135 They found that amphiphilic imines can reversibly assemble into spherical micelles and cylindrical micelles (Figure 1.16). Since the amphiphilic imine is stabilized by forming a supramolecular assembly, the formation of micelles promotes further formation of the imine, resulting in the growth of the aggregates. As the micelles grow, they become unstable, which causes them to split into smaller aggregates. In this case, the reproducing entity is the entire micelle. In the dynamic combinatorial library the imines that were able to form nanostructures were formed selectively.
Figu Our gro function chains c generati oxidatio of the m grow lon fibers c combina replicatio template replicato environm can exhi re 1.16. Imine oup serendi alized buildi composed of on of β‐shee n of these b macrocyclic c ng enough, t creates mor atorial library
on. The aut e product w ors from D ments139 and bit parasitic e driven self‐a ipitously dis ing blocks in f alternating ets and an a building block compounds s they become re fiber end y toward a s tocatalytic n which was fo DCLs can d pre‐existing phenomena assembly of di scovered se n 2010.137 Th g hydrophob aromatic dith ks in water, stacks into f e susceptible ds, thereby single produ ature of thi ound to acce
be affected g replicators a similar to b ifferent autoc elf‐replicatin he building b bic and hydr
hiol core for first a mixtu ibers due to e to shear s y propelling ct. The fiber s process w elerate the r d by temp s.140,141 More iological syst catalytic nanos g molecule blocks are fu rophilic amin thiol‐disulfi ure of macro o the format tress. Mecha the replic r‐growth‐bre was confirme rate of the r plates,138 m eover, these tems.142 structures. Ad s in DCLs unctionalized no‐acid resid de exchange ocyclic disulfi ion of β‐she anically indu ation proce eakage cycle ed by adding reaction. The mechanical a dynamic sel dapted from r made from d with short dues to facil e (Figure 1.1 ides forms. T eets. When t
uced breakag ess in the
enables exp g a small am e emergenc agitation,137 lf‐replication ef.136 m dithiol t peptide litate the 17). Upon Then one the fibers ge of the dynamic ponential mount of e of self‐
solvent n systems
1.5 Aim
So far, m Howeve self‐repl Darwinia molecule studying efficient applicati One of t the princ principle applicati more int Figure 1.17m and outl
many synthe r, most of t icating syst an evolution es. After ma g complex sy method fo ions have be hese involve ciple has bee e. In additioion is to mer teresting dyn . Emergence o
ine
etic self‐repli hese system ems are un n. In the fi ny years of ystems. It re or construc een develope es the use of en proven m on, since DC rge subsyste namic behav of self‐replicat icating and f ms rely on co nable to greld of folda developmen elaxes the d ting comple ed by using D f DCC to achi many years a CC has the ems with diff viors and pro tors from disu folding syste omplex mult row expone amers, only nt, DCC has b demand for ex structure DCC and the ieve the synt ago, there ha ability to li ferent chara operties. ulfide based D ems have be ti‐step synth ntially whic few skelet become a po multi‐step s es and dyn ere is still mu thesis of com ave been no ink multiple cteristics to DCLs. Adapted een develope hesis. In add
h is particu ton structur owerful tool synthesis, pr amic proce uch room for mplex folded reports that e subsystem build new co d from ref.139
ed in the pa ition, most ularly impo res can form
for construc roviding a d esses. So fa r new develo structures. t go beyond s, another omplex syst ast years. synthetic rtant for m folded cting and irect and ar, many opments. Although proof of potential ems with
Self‐replication is one of the most important ingredients in the origin of life, and self‐replicating molecules are a promising starting point for the de‐novo synthesis of life. Folding is the process by which proteins and nucleic acid strands acquire a three‐dimensional structure required for function. This thesis intends to capture the processes of self‐replication and folding individually, or combined by using dynamic combinatorial chemistry. We first describe how to use dynamic combinatorial chemistry to construct complex folded structures. By making use of simple building blocks, we have achieved the selective assembly of remarkably complex folded structures. We also combined the processes of folding and self‐replication in a single system, giving rise to the first such example in synthetic systems.
In Chapter 2, we describe how a dynamic combinatorial selection approach allows access to a foldamer of remarkable complexity constituted by 15 identical peptide‐nucleobase building blocks. The folded structure has a complex secondary and tertiary structure and can emerge autonomously and spontaneously from a dynamic combinatorial library. Folding drives the highly selective (95% yield) synthesis of this remarkable stable folded structure from a mixture of interconverting molecules of different ring sizes in a one‐step process. Structural characterization reveals that noncovalent interactions such as π‐π stacking and hydrogen bonding play a key role in the stabilization of this complex molecule.
Following the results in Chapter 2, we synthesized a series of new building blocks by replacing the peptide‐nucleobase motif with a simple dipeptide subunit. In Chapter 3, we describe a family of complex folded structures that emerged from dynamic combinatorial libraries made from these building blocks. Like the peptide‐nucleobase foldamer described in Chapter 2, the formation of dipeptide foldamers is also spontaneous and selective. The introduction of hydrogen bonding sites on the structure of the dipeptide building blocks can significantly affect the formation of folded structures, leading to the emergence of macrocycles of different sizes (9‐23mers).
Having established the method for the selective formation of complex folded structures from dynamic combinatorial libraries, we tried to operate the processes of folding and self‐replication in a single system. In Chapter 4, a new dynamic combinatorial library is set up by mixing the building block that is capable of forming folded structures with another building block that can undergo self‐ replication. The results show no self‐sorting between self‐replicator and foldamer in this mixed system. Instead a series of mixed‐building‐block self‐replicators was obtained. Unlike other nucleic‐ acid self‐replicating systems that rely on base pairing, the emergence of the new self‐replicators depends on the ratio of the building blocks and the assembly into ordered supramolecular
nanostructures. In addition, selective auto‐ and cross‐catalysis in multicomponent systems are also described in this chapter.
In Chapter 5, we further explored the possibility of self‐sorting of self‐replicators and foldamers in mixed building block systems. By simply changing the structure of the peptide building block, the processes of self‐replication and folding were found to occur simultaneously in a single dynamic library. The results show that the emergence of self‐replicator or foldamer is determined by the ratio of the building blocks that make up the dynamic library. The emergence of the self‐replicator can promote the formation of the complex folded structures. Furthermore, transient formation of a self‐ replicator can also be achieved by adjusting the ratio of the building blocks. Finally, Chapter 6 gives a summary of this thesis and places the results in a broader perspective.
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