Cyclic Pep ides
Molecula Plumbing o Bend Sel -Assembling Pep ide Nano ubes
Fede ica No elli, Ma cos Vilela, An a Paz, Manuel Amo n, and Juan R. G anja*
Abs ac : Ligh -induced molecula piping o cyclic pep ide
nano ubes o o m ben ubula s uc u es is desc ibed. The
p ocess is based on he [4
+
4] pho ocycloaddi ion o an h a-
cene moie ies, whose s uc u al changes de i ed om he
in e digi a ed la disposi ion o p ecu so s o he co espond-
ing cycloadduc moie ies, induced he geome ical modi ica-
ions in nano ubes packing ha p o okes hei cu a u e. Fo
his pu pose, we designed a new class o cyclic pep ide
nano ubes o med by b- and a-amino acids. The p esence o
he o me p edisposes he pep ide o s ack in a pa allel ashion
wi h he b- esidues aligned along he nano ube and he
homogeneous dis ibu ion o an h acene pendan s.
In oduc ion
Ligh is he li elihood ha p o ides no only he mal
hea ing suppo bu also igge s a a ie y o essen ial
ans o ma ions o li ing o ganisms.[1] An a ay o chemical
p ocesses, i.e., bioene gy p oduc ion h ough pho osyn hesis,
he b eakage o o ma ion o chemical bonds, o changes in
con o ma ion, a e pi o al pho oinduced e en s o li ing
o ganisms.[2] The isual ansduc ion pa hway based on
hodopsin pho oisome iza ion is one o he ema kable
examples a his espec . Rhodopsin is he bina y complex
in ol ed in isual ansduc ion h ough he isome iza ion o
e inal, om 11-cis- o all- ans-isome , upon ligh i adia ion
(Scheme 1a).[3] Such isome iza ion gi es ise o opsin con-
o ma ional changes ha induce he neu onal exci a ion
in ol ed in he isual pa hway. In ecen yea s, sup amolec-
ula p ocesses ha e deal wi h dynamic sys ems ha comple-
men he o iginally mo e s a ic complexes based on he mo e
s able he modynamic s uc u e. The e o e, sys em chemis y,
a om equilib ia p ocesses, kine ic aps, dissipa i e assem-
bly o dynamic lib a ies, ha e eme ged as new ools o
de eloping unc ional sup amolecula sys ems.[4] In his sense,
esponsi e ma e ials a e a pa adigm in ma e ials sciences due
o he abili y o modi y hei p ope ies in esponse o
ex e nal inpu s.[5] Thus, ma e ials sensi i e o pH, edox, ionic
s eng h, o empe a u e changes ha e been pu sued in he
las yea s, seeking a a ie y o unc ions and applica ions. In
his espec , ligh - esponsi e ma e ials ep esen a class o
e sa ile ma e ials in which he use o app op ia e wa eleng h
can induce on-demand changes in hei shape, size, o
con o ma ion.[4a,6] In gene al, isome iza ions (E/Z), elec o-
cycliza ions, o cycloaddi ion p ocesses p o ide he equi ed
molecula modi ica ions o change he ma e ial p ope ies
(Scheme 1b).[7]
Tube-shaped ma e ials a e e y use ul componen s, bo h
a he mac oscopic and mic oscopic le els, as s uc u al
componen s o o con eying lowing subs ances hanks o he
hollow s uc u e and ligh ness. In mos cases, o imp o e he
ube unc ions, plumbing ac ions o pipe elbows o bends a e
equi ed. A he molecula le el, i is s ill equi ed o c ea e
his kind o adap e s o enginee ing on-demand “molecula
plumbing p ocesses” o adap he nano ube shape o he
su ounding media o imp o e i s applica ions.[8,9]
Sel -assembling cyclic pep ide nano ubes (SCPNs) a e
a class o sup amolecula polyme s made by he o de ed
piling up o pep ide mac ocycles.[10] A la ge a ie y o
applica ions ha e been de eloped since i s disco e y in
1993.[11] Especially ele an a e hose ela ed o ion and
molecula anspo in which he p ope ies o he nano ube
po e p o ide some selec i i y.[12] Kine ic s udies sugges ha
nano ube o ma ion is a coope a i e p ocess in which once
nano ube o ma ion is igge ed, hey con inue g owing,
helped by he in e - ube (c ys al la ice) in e ac ions, making
di icul o con ol nano ube leng h and packing.[13] Al hough
some s eps owa ds his end ha e been achie ed in he las
Scheme 1. Ligh -induced geome ical changes o a) Rhodopsin,
b) azo,[15] and spi opy an[16] compounds as ini ia o s o molecula
changes, and c) he nano ube plumbing echnology de eloped in his
wo k based on an h acene [4
+
4] pho odime iza ion.
[*] D . F. No elli, M. Vilela, A. Paz, D . M. Amo n, P o . D . J. R. G anja
Cen o Singula de In es igacin en Qumica Biolxica e Ma e iais
Molecula es (CIQUS) and O ganic Chemis y Depa men
Uni e sidade de San iago de Compos ela
15782 San iago de Compos ela (Spain)
E-mail: juan [email p o ec ed]
Suppo ing in o ma ion and he ORCID iden i ica ion numbe (s) o
he au ho (s) o his a icle can be ound unde :
h ps://doi.o g/10.1002/anie.202107034.
2021 The Au ho s. Angewand e Chemie In e na ional Edi ion
published by Wiley-VCH GmbH. This is an open access a icle unde
he e ms o he C ea i e Commons A ibu ion Non-Comme cial
NoDe i s License, which pe mi s use and dis ibu ion in any
medium, p o ided he o iginal wo k is p ope ly ci ed, he use is non-
comme cial and no modi ica ions o adap a ions a e made.
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yea s by using CPs/polyme s hyb ids,[14] u he con ol in
hese nano ube s uc u al pa ame e s a e s ill equi ed.
Recen s udies by us and o he s ha e opened he
oppo uni y o c ea e s imuli e e sible SCPN s uc u es ha
migh help o de elop a i icial cell cy oskele ons and o he
dynamic sca olds.[17] Fo hese pu poses, we ha e combined
he in e pep ide in e ac ions based on amide hyd ogen-
bonded ne wo ks and he p–pin e ac ions o py ene (Py )
moie ies o igge nano ube o ma ion in aqueous o d ople
media.[18,17b] In hese pep ides, he in e digi a ion o he
a oma ic moie ies helps no only in he CP s acking o o m
nano ubes bu also p omo es he o ma ion o small bundles
h ough a hie a chical sel -assembling p ocess (Scheme 2). In
his s a egy, he a yl g oup can be o hogonally in oduced a
he end o he p ocess by condensing a yl aldehydes wi h CPs
bea ing an alkoxyamine moie y.[18,17b] Al hough he inco po-
a ion o he a oma ic ing acili a es he s acking o CP ings,
he dis ance di e ences be ween he p-s acking (3.3–3.5 )
and b-shee pep ide s ands (4.7 ) also acili a e he in e -
ube packing by in e digi a ing hei a oma ic moie ies. In his
ega d, we ha e shown ha ime ic sil e clus e s help o
s abilize he ubula s uc u e h ough he in e cala ion on he
py ene packing.[19] The e o e, a yl pendan s ep esen an
addi ional checkpoin o une nano ube o ma ion and
p ope ies. We en isaged ha an h acene (An ) moie y could
also be used, dampening he hyd ophobic e ec in he
assembly p ocess while main aining good luminescen beha -
io and s abili y.[20] Besides, his g oup is a pho oac i e
ma e ial ha can dime ize using app op ia e wa eleng h,[21]
being used in a ious sup amolecula con ex s, especially o
c oss-linking pu poses.[22] We en isioned ha he change in
olume and dimensions be ween he s acked dime o An
and he co esponding pho odime could be used o induce
changes in he SCPN packing and p ope ies (Scheme 2).[23]
Such nano ube mo emen could be implemen ed in de elop-
ing pho osensi i e ma e ials.[24] The e o e, we specula ed ha
he use o his e e sible p ocess could p o ide a new ool o
modi y nano ube shapes and unc ions. He ein, we p o ide
he i s s ep o he on-demand molecula plumbing o
pep ide nano ubes.
Resul s and Discussion
To ca y ou his wo k, we decided o c ea e a new class o
pep ide hyb ids made o a- and b-amino acids o p ecisely
con ol no only he in e pep ide egis e bu also o con ol
he b-shee ype (Scheme 3).[25,26] Fo his pu pose, we used
he o iginal D,L-al e na ing sequence[11] combined wi h wo
b-amino acids. In he equi ed la con o ma ion, his ype o
esidues wi h an e en numbe o ca bons be ween he
ca bonyl and NH moie ies p edispose he amide g oups
(NH and C=O) o poin ou in he opposi e way.[27] The e o e,
he inse ion o hese b- esidues should induce he CPs o
s ack, o ming pa allel b-shee s uc u es.[28] The inco po a-
ion o he His esidues was aimed o p o ide solubili y o he
pep ide and sel -assembling ulminan capabili y due o i s
ioniza ion s a e changes a almos neu al pH. Besides, a Lys
modi ied wi h a hyd oxylamine ace yl moie y was place a he
opposi e side o he b- esidues o allow he inco po a ion o
he an h acene-9-ca baldehyde h ough an oxime bond.
Consequen ly, in he p oposed pa allel model, he a ene
s acking and he b- esidues would p o ide nano ubes in which
each esidue would be aligned wi h i sel along he ubula
s uc u e (see nano ubes models in Scheme 3). In his
o ganiza ion, His (as illus a ed in he inse ), Se o Gln side
chains could also pa icipa e in s abilizing he ubula
s uc u e by o ming addi ional hyd ogen bonds assis ed, in
some cases, by wa e molecules.
CP2 was p epa ed by solid-phase me hods ollowing he
s a egy p e iously epo ed by ou g oup (Suppo ing
Scheme 2. Sup amolecula hie a chical p ocess esponsible o SCPN
o ma ion. Righ inse , p oposed changes in dimensions o an h acene
moie ies upon pho odime iza ion.
Scheme 3. S uc u e o cyclic pep ides and models o nano ube
o ma ion guided by he s acking o an h acene moie y and b- esidues
(in g een). Bo om inse : p oposed E/Zisome o oxime linke o
explain he obse ed An ing cu en shielding o Lys side-chain
signals. Top inse : p oposed His-His in e ac ion media ed by a wa e
molecule.
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In o ma ion, Scheme S1).[17b,18,29] The esul ing pu e pep ide
was condensed wi h he an h aldehyde by mixing bo h
componen s in DMSO a 60
8
C o p o ide CP3. The HPLC
analysis o his pep ide showed one single peak (Figu e S1),
con i ming i s pu i y, which did no equi e u he pu i ica-
ion. Ou ini ial s udies we e di ec ed o demons a e he
abili y o his new D,L-a,b-CP hyb id o assemble in o
nano ubes bo h in solu ion and solid-s a e. CP3 was soluble
in double-dis illed wa e , whose esul ing pH (3–5) depended
on CP concen a ion as a consequence o i s p o ona ion s a e
a e he HPLC pu i ica ion. A neu al pH (Hepes bu e ),
he solubili y is educed, s a ing o p ecipi a e a concen-
a ions abo e 400 mM. The luo escence spec a a na i e pH
showed a band cen e ed a ound 475 nm whose in ensi y
sligh ly dec eases as pH is aised un il a c i ical poin (pH 7.3),
a e which i inc eases again upon u he base addi ion
(Figu e S2). Such beha io migh be explained by he
imidazolium ing dep o ona ion as he pH inc eases ha
migh igge he CP sel -assembly. This piling up o CPs mus
cause he s acking o he a oma ic luo opho e and, con-
sequen ly, leading o highe luo escen ou pu . Expe imen s
using Nile ed (NR) we e also ca ied ou o de e mine he
c i ical agg ega ion concen a ion (cac), he lowes concen-
a ion in which CP assembling s a s o ake place. NR is
a hyd ophobic dye ha exhibi s a signi ican inc ease oge he
wi h a blue shi o he maximum emission wa eleng h when
inco po a ed in hyd ophobic en i onmen s.[30] The luo es-
cence expe imen s o CP3 a di e en concen a ions (6–
500 mM) in Hepes (10 mM, pH 7) in he p esence o NR
(1 mM) allowed o es ima e a cac a ound 50 mM (Figu e 1a
and S3). A simila alue (45 mM) was ob ained using he ThT
p obe in he same condi ions (Figu e S4),[31] sugges ing ha
he b-shee o ma ion akes place oge he wi h hyd ophobic
packing when he agg ega ion occu s.
FTIR measu emen was ca ied ou o in es iga e he CP
s uc u e (Figu e S5). The FTIR spec um on a eeze-d ied
powde a e basi ica ion suppo s he o ma ion o a pa allel
b-shee s uc u e wi h a s ong peak a 1633 cm1and
a shoulde a 1664 cm1.[32] The amide A band a 3293 cm1
is highly indica i e o a well-es ablished ne wo k o back-
bone-backbone hyd ogen bonds.[33] CD s udies we e also
pe o med o e alua e he pH-induced sup amolecula sel -
assembly (Figu e 1b). No CD signals we e de ec ed a na i e
pH (ca. 3.6). On he con a y, a s ong Co on e ec was
obse ed a 255 nm and, o a lesse ex en , o he An band a
340–400 nm as he pH inc eases. Such an ou come sugges s
he o ma ion o long- ange-o de ed sup amolecula assem-
blies as he pH inc eased, wi h he concomi an ans e o
chi ali y om he pep ide o he an h acene uni . Plo ing he
CD signal a 275 nm as a unc ion o he pH (Figu e S6)
p o ided mean alues o pKa=7.3 and a Hill coe icien o
n=1.60.3, sugges ing a coope a i e sel -assembly p ocess.
STEM mic oscopy was employed o e alua e he sel -
assembled s uc u e o CP3 a di e en pH (Figu e 1c). As
men ioned abo e, a na i e pH (3–5), he deposi ion o CP3
solu ion (350 mM) on Cu g ids p o ided mainly amo phous
agg ega es o , o a lesse ex en , small ubes wi h diame e s o
abou 2–3 nm and leng hs anging be ween 150–200 nm
(Figu e S7). This beha io was expec ed since he p o ona ion
o he His side chains and he co esponding epulsi e
in e molecula in e ac ions o cha ged imidazolium ings
would p eclude he build-up o nano ubes. On he o he hand,
a neu al pH (350 mM), indi idual SCPNs wi h a diame e o
app oxima ely 2–3 nm and leng hs o a ew mic ons oge he
wi h bundles o hem wi h an a e age diame e o ca. 5–6 nm
we e obse ed (Figu e 1c). AFM analysis also co obo a ed
hese dimensions (Figu e 1d and S8). Nano ube bundles mus
a ise om in e molecula an h acene-an h acene in e ac ions
and he coexis ence o bo h ypes o s uc u e co obo a e he
exis ence o he men ioned hie a chical assembling p ocess
illus a ed in Scheme 2. The e o e, he neu aliza ion o
aqueous media os e s he o ma ion o a unique syne gis ic
in e play be ween hyd ogen bonding, hyd ophobic, and p-p
in e ac ions wi h subsequen o ganiza ion in hie a chical
ubula a chi ec u es.
Once con i med he nano ube o ma ion, we s a ed o
e alua e he An pho odime iza ion.[21] The e o e, we decided
o in es iga e i upon UV i adia ion a 350 nm a di e en
pH (Figu e S9): acidic (1.85), na i e (4.95), and neu al
(Hepes, 10 mM). The degassed solu ions o CP3 (250 mM)
we e i adia ed, and he p ocess was ollowed by he
educ ion in abso p ion o he band a 386 nm due o he
loss o a oma ici y o an h acene moie y upon he [4
+
4]
pho ochemical cycloaddi ion.[34] The eac ion p oceeds
smoo hly a pH 7 a e 90 min. A na i e (4.95) and acidic
Figu e 1. a) NR (1 mM) luo escence spec a a di e en concen a-
ions o CP3 (10 mM Hepes, pH 7); b) O e laid CD spec a o CP3
aqueous solu ion a di e en pH; c) STEM mic og aphs achie ed by
deposi ion om solu ions o CP3 (350 mM, pH 7) on Cu g ids. S aining
was ob ained wi h 2% w/ phospho ungs ic acid (PTA). d) AFM
mic og aphs o CP3 (350 mM, pH 7) on a silicon wa e subs a e. The
heigh p o iles ( igh ) we e achie ed along he colo lines shown in he
image.
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condi ions (1.85), he con e sion was smalle , 80% and 60%,
espec i ely. The kine ic s udies (Figu e S10) allowed es i-
ma ing a eloci y cons an k1o 0.14 min1a neu al pH, i e
imes as e han o acidic condi ions (0.03 min1a pH 1.85).
These esul s sugges ha An p eo ganiza ion, a o ed a he
condi ions in which nano ubes a e al eady o ms, speeding up,
as expec ed, he [4
+
4] cycloaddi ion. To con i m ha hese
di e ences in a es a e ela ed wi h nano ube s uc u e and
no wi h media condi ions, a model an h acene de i a i e
(An 1, Scheme 4) was p epa ed and UV i adia ion a
di e en pH (3.5 and 7.0) we e ca ied ou (Figu es S11 and
S12). The eac ions o model An 1 a bo h pH a e slowe han
o CP3. Addi ionally, and con a y o wha was obse ed o
CP3, he eac ion is slowe a neu al pH han a acidic media.
This con i ms he impo ance o he nano ube induced
p eo ganiza ion o An moie ies o acili a e he pho odime-
iza ion.
HPLC analysis o he mix u e a pH 7, p o ided in o ma-
ion ega ding p oduc s o ma ion (Figu e S13). In addi ion o
he s a ing ma e ial, ou new peaks we e obse ed du ing
he i adia ion p ocess. One o hem (min 8.59, Figu e S13)
aised e y as a he ini ial s age o i adia ion o dec ease
la e as he o he h ee p oduc s s a ising. Ms analysis
(Figu e S14) shows ha his p oduc has he molecula weigh
o he monome , whose abso p ion spec a coincide wi h
an h acene de i a i es (Figu e S15a). These sugges ha his
p oduc mus be a s e eome o s a ing ma e ial (CP3Z).
Howe e , he molecula weigh o he o he h ee p oduc s
(Figu e S14) coincides wi h dime ic s uc u es (D3) and
whose UV spec a also con i m he [4
+
4] cycloadduc
s uc u es (Figu e S15b). Addi ionally, o ule ou he o -
ma ion o pho ooxygena ed p oduc s,[35] he eac ion was also
ca ied ou in an oxygen-equilib a ed solu ion a pH 7
(Figu e S16). Unde hese condi ions a a ie y o new
p oduc s, some o hem assigned o he co esponding
endope oxides and/o an h oquinones, we e o med. Any o
hese p oduc s we e no de ec ed unde he oxygen- ee
i adia ion condi ions.
The NMR analysis (Figu e S17) o he newly o med
monome (CP3Z) sugges ed ha he he modynamic oxyme
E-isome is pho o- ans o med in o he Z- o m[36] ha is
kine ically s able emaining in his geome y e en when i s
aqueous solu ion is allowed o equilib a e on he bench o
a ew days. The obse ed shielding e ec on he Lys side-
chain p o ons, NH a 6.92 ppm o me hylenes a 1.00 (gCH2)
and 1.17 (dCH2) ppm, de i ed om he ing cu en o An
moie y (inse Scheme 3) sugges ha he hyd ophobic con-
ac s mus s abilize his o m (Figu e S17b).
In ou ini ial e alua ion, we conside ed he o ma ion o
wo ypes o dime s,[37] he head- o-head (D3hh) and he head-
o- ail (D3h ), based on whe he he eac ion occu s h ough
in e - ubula o in a- ubula p ocesses (Scheme 4). Howe e ,
NMR analysis o he esul ing dime s, ob ained in a 1:2:4
a io, ules ou he o ma ion o isola ion o D3hh based on he
obse ed c oss-signal in he HMBC spec a be ween H10 and
he b idgehead ca bon C9(Scheme 4), see suppo ing in o -
ma ion o u he de ails. In o de o disca d he o ma ion o
he head- o-head dime (D3hh) ha because o i s ins abili y
could e e unde he analysis condi ions, a new expe imen
was ca ied ou using combina ion o i adia ion and da k
cycles (Figu e S18).[38] The o ma ion o he head- o-head
pho odime can be analyzed by ollowing he changes o he
an h acene abso p ion band (386 nm) upon sequen ial cycles
o i adia ion a 350 nm o a sho ime ollowed by an
equilib a ion ime in he da k a 298 K. Unde hese
condi ions no e u n o he an h acene abso p ion band was
obse ed con i ming ha D3hh was no o med unde hese
condi ions. Consequen ly, all h ee isome s a e head- o- ail
de i a i es di e en ia ed by he geome y o oxyme bond:
he E,E-, Z,Z- and E,Z-de i a i es. The complexi y o he
spec um o he majo isome (8.26 min) compa ed wi h he
o he wo sugges s ha his co esponds o he E,Z-D3h
(Figu e S17c). The Z,Z-D3h was assigned o he mino
p oduc (5.37 min) acco ding, again, o he shielding e ec
o he Lys side-chain p o ons (Figu e S17e). The e o e, in he
in e ubula cycloaddi ion p ocess, i seems ha he mo e
a o able packing is he one in which one Z-isome is close o
he E-de i a i e.
These dime s can be e e ed o he An s uc u e by
hea ing he aqueous solu ions con aining each o he dime s
(250 mM) o 800 min a 80
8
C. The p ocess was ollowed by
UV-VIS (Figu e S19) and HPLC (Figu e S20) analysis. In e -
es ingly, each o he dime s e e ed in o he co esponding
monome s main aining hei hyd azone geome y wi hou
isome iza ion o he mo e s able o m. The s abili y o he
co esponding dime s (Figu e S19) is qui e di e en , while
Z,Z-D3h only p o ided a 12% o he CP3Za e 800 min o
hea ing, he he e odime ic o m (E,Z-D3h ) p o ided almos
a 50% o ee an h acene de i a i es (CP3Eand CP3Z).
A e con i ming he dime iza ion p ocess, we decided o
s udy he sel -assembly p ocess a he mac oscopic le el.
The e o e, solu ions o CP3 (350 mM) a neu al pH we e
analyzed by epi luo escence mic oscopy (Figu e 2 and S21).
Unde hese condi ions, b igh and g een needle-shaped
s uc u es (11.5–2 mm) we e obse ed deno ing ha he pH
igge ed hie a chical assembly p ocess was main ained om
he nano ubes o he mic o-scale ubula a chi ec u es.
No ably, by inc easing he i adia ion ime, he luo escence
emission o he bundles swi ched i e e sibly om g een o
blue (Figu e 2b and S22). Besides, he change in luo escence
Scheme 4. Ligh -induced dime iza ion s udies o CP3 and p oposed
model o he o ma ion o he ini ially p oposed dime s, he head- o-
head (D3hh) de i ed om an in a ubula p ocess and he head o ail
(D3h ) gene a ed by he in e - ubula in e ac ions.
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emission was associa ed in he la ge ib es wi h a ligh -
induced bending mo ion o he ods (Figu e 2c). The di e -
ences in eac ion ime obse ed be ween he bulk solu ion
(90 min) wi h he single ibe (30 s) mus be ela ed wi h he
di e ences be ween he in a-bundle pho ochemical eac ion
and he combina ion o in a-bundle and in e - ubula
dime iza ion ha mus ake place in solu ion. A his espec ,
a he CP concen a ion used in he pho odime iza ion
eac ion (250–350 mM) he single SCPNs a e in equilib ia
wi h nano ubes bundles (Figu e 2c) as can be in e ed om
he concen a ion dependen expe imen s ca ied ou by UV/
Vis and CD wi h a model pep ide bea ing a py ene moie y
(Figu e S23).[39] The expe imen s ca ied ou by UV/Vis in he
p esence o NR p o ide in o ma ion abou nano ube o ma-
ion, while he appea ance o he Co on e ec a 340–400 nm
mus be ela ed wi h he nano ube bundling. The cac
de e mined o each echnique di e in almos one o de o
magni ude (10 mM and 100 mM), sugges ing ha hey a e
measu ing di e en agg ega ion e en s.
The esul ing i adia ed solu ions we e also e alua ed by
STEM (Figu e 2d and S24). To ou deligh , zigzagging-shaped
ubula s uc u es we e obse ed, sugges ing ha he ligh -
induced p ocess p o ided s uc u es ha e ained he ubula
s uc u e bu a a ie y o elbow in hese hollow ibe s we e
obse ed. The e o e, he ligh -induced an h acene dime iza-
ion is able o change he in e -nano ube packing, o cing o
bend o sa is y he s uc u al es ic ions induced by he
cycloadduc o ma ion.
Conclusion
We ha e shown a new class o cyclic pep ide hyb ids
designed o s ack in a pa allel ashion o o m nano ubes ha
can bend as a esul o a ligh s imulus. Unde hese
condi ions, he an h acene pendan ha bea s each cyclic
componen pho odime ize, and he changes in dimensions
ha accompanies his cycloaddi ion pe haps oge he wi h E-
Zoxyme isome iza ion induce s uc u al changes in he
nano ube packing ha o ce he nano ube o cu e. We
en isage ha hese ligh -induced dynamic changes in shape
can enable new unc ions, pa icula ly in a biological con ex .
Acknowledgemen s
This wo k was suppo ed by he Spanish Agencia Es a al de
In es igacin (AEI) (CTQ2016-78423-R and PID2019-
111126RB-100), he Xun a de Galicia (ED431C 2017/25 and
Cen o singula de In es igacin de Galicia acc edi a ion
2019–2022, ED431G 2019/03), and he Eu opean Union
(Eu opean Regional De elopmen Fund—ERDF). We also
hank he ORFEO-CINCA ne wo k and Mineco (CTQ2016-
81797-REDC, and RED2018-102331-T).
Con lic o In e es
The au ho s decla e no con lic o in e es .
Keywo ds: cyclic pep ides · molecula plumbing · nano ubes ·
pho odime iza ion · sel -assembly
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py ene moie y (CP3P) i s p ecipi a ion a concen a ion highe
o 400 mM did no allowed o p ecisely es ima e he c i ical
agg ega ion concen a ion o bundle o ma ion in he CD
expe imen s.
Manusc ip ecei ed: May 26, 2021
Accep ed manusc ip online: June 29, 2021
Ve sion o eco d online: &&
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Resea ch A icles
Cyclic Pep ides
F. No elli, M. Vilela, A. Paz, M. Amo n,
J. R. G anja*
&&&& —&&&&
Molecula Plumbing o Bend Sel -
Assembling Pep ide Nano ubes
Ligh -induced molecula plumbing o
cyclic pep ide nano ubes based on
a[4
+
4] cycloaddi ion o an h acene moi-
e ies is desc ibed. The geome ical
changes induced by he o ma ion o he
cycloadduc ans e o he sup amolec-
ula agg ega e s uc u al cons ains ha
o ce he nano ube o bend.
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