FAKULTET ZA FIZIČKU HEMIJU

Univerzitet u Beogradu

Sistemska hemija
i
polimeri
DRUŠTVO FIZIKOHEMIČARA
SRBIJE
SEKCIJA Z A FIZIČKU HEMIJU
MAKROMOLEKULA
maj, 2017. godine dr Vladimir Marković
  Sistemska hemija je relativno mlada savremena disciplina koja se može shvatiti kao:

„interdisciplinarni pristup prebiotičke i supramolekularne hemije da, uz pomoć

kompjutacionih i teorijskih metoda i koncepata teorijske hemije, biologije i nauke o
kompleksnim sistemima, omogući proučavanje različitih vidova integracije dinamičkih
supersistema koji sadrže bar jedan autokatalički podsistem“.

 S obzirom na temu i cilj proučavanja, polimeri zauzimaju važno mesto u sistemskoj

hemiji, omogućavajući dizajn i produkciju funkcionalnih i kompleksnih materijala i
struktura koje poseduju kvalitete nadražljivosti, modularnosti, adaptibilnosti,
autonomnosti.

- Uloga polimera u savremenim istraživanjim u sistemskoj hemiji biće ilustrovano pomoću

nekoliko skorašnjih i karakterisitčnih primera koji demonstriraju njihovu nezaobilaznu
ulogu u kreiranju „pametnih“ materijala i struktura budućnosti.

Postma et al. (2017) Preprogramming Complex Hydrogel Responses using Enzymatic Reaction Networks , Angewandte Chemie Int . Ed. Engl., 56, 1794.
 Preprogramming Complex Hydrogel Responses using Enzymatic Reaction Networks
Tr: trypsin
Cr: chymotrysin
Arginine res. Linker 4 : poly(ethylene glycol)-bis-maleimide

Arginine res.
Serine res.
Serine res.

Leucine res.

Gel–liquid–gel transitions

- The initial polyacrylamide hydrogel contains crosslinks 1 (C1) and a copolymerized thioester 3.
-C1 is quickly degraded by Tr

- thioester 3 is cleaved slowly by Tr or quickly by Cr to produce thiols which subsequently form new
crosslinks 2 (C2) after reacting with a linker 4 (poly(ethylene glycol)-bis-maleimide).

Postma et al. (2017) Preprogramming Complex Hydrogel Responses using Enzymatic Reaction Networks , Angewandte Chemie Int . Ed. Engl., 56, 1794.
 Preprogramming Complex Hydrogel Responses using Enzymatic Reaction Networks

Gel–liquid–gel transitions

Gel 1 Liquid Gel 2

t=0 h: Cone-shaped gel (200 µL volume) containing t=0 to t=20 h: A gel–liquid–gel transition occurs
C1 and thioester 3 is soaked with linker 4 during which the shape of the gel changes, and the
(poly(ethylene glycol)-bis-maleimide), after which Tr magnetic stirring bar is encapsulated.
is applied ([Tr]0=5 µm).
- All experiments were performed in
100 mm Tris-HCl buffer pH 7.5 with 20 mm CaCl2.

Postma et al. (2017) Preprogramming Complex Hydrogel Responses using Enzymatic Reaction Networks , Angewandte Chemie Int . Ed. Engl., 56, 1794.
 Preprogramming Complex Hydrogel Responses using Enzymatic Reaction Networks

Introducing an enzymatic reaction network in

the hydrogel

strong inhibition

weak inhibition

-Trypsin (Tr) catalyzes its own formation by activating trypsinogen (Tg), creating a positive feedback
loop.

- Tr also activates chymotrypsinogen (Cg) to form chymotrypsin (Cr).

- Soybean trypsin inhibitor (STI) inhibits Tr (strongly) and Cr (weakly) (indicated by the thickness of the
inhibition arrows).
Postma et al. (2017) Preprogramming Complex Hydrogel Responses using Enzymatic
Reaction Networks , Angewandte Chemie Int . Ed. Engl., 56, 1794.
 Preprogramming Complex Hydrogel Responses using Enzymatic Reaction Networks

Phase diagram of [Cg] vs. [Tr]0

-Blue square with an asterisk

denotes experiments conducted at
[Tr]0= 7, 20, or 50 µm, all of which
show gel–liquid–gel transitions.

- Phase diagram of [Cg] vs. [Tr]0 obtained - Experiments are shown in squares.
by mathematical modelling (ordinary
differential kinetic equations). - In all cases: [Tg]0= 80 µm and [STI]= 1.9 µm.

Postma et al. (2017) Preprogramming Complex Hydrogel Responses using Enzymatic

Reaction Networks , Angewandte Chemie Int . Ed. Engl., 56, 1794.
 unstirred
(without mechanical
agitation)

stirred

UPLC analyses of DCLs made from 6.0 mM

building block1 in a 9:1 mixture of aqueous
Dynamic Combinatorial Chemistry of Building Block 1. borate buffer (50 mM, pH 8.2) and DMF, (A)
without agitation and (B) stirred at 1200 rpm.

Komáromy et al. (2017) Self-Assembly Can

Direct Dynamic Covalent Bond Formation toward
Diversity or Specificity, Journal American
Chemical Society, 139, 6234.
 (A) Change of the product distribution with time in a DCL
prepared of building block 1, showing the characteristic
sigmoidal growth of the hexamer.

Autocatalytic nature of the formation of

the hexamer: seeding experiments

(B) Change of the relative concentration of

the hexamer of 1 in a DCL:
- without hexamer seeding (squares)
- upon hexamer seeding with 5.0% (circles)
Dynamic Combinatorial Chemistry of Building Block 1.
- upon hexamer seeding with 10% (triangles)

Komáromy et al. (2017) Self-Assembly Can Direct Dynamic Covalent Bond Formation
toward Diversity or Specificity, Journal American Chemical Society, 139, 6234.
 Building Block 1

self-
assembling
into well-
defined
nanoribbons
Dynamic Combinatorial Chemistry of
and
Building Block 1.
nanoplatelets

Building Block 2

Simplified Potential Energy Landscape of Dynamic

Combinatorial Libraries of Building Block 1 in Water.

Komáromy et al. (2017) Self-Assembly Can Direct Dynamic Covalent Bond Formation
toward Diversity or Specificity, Journal American Chemical Society, 139, 6234.
 Compartmentalized Out-of-Equilibrium Enzymatic Reaction Network for Sustained Autonomous Movement

stromatocyte

Polymero-
somes LO: L-lactate
LDH: L-lactate
dehydrogenase oxidase

Rational design and experimental assembly of a compartmentalized metabolic network.

(A) :Nanoreactors containing four enzymatic cycles which are able to convert glucose and phosphoenolpyruvate (PEP)
into movement of the construct.

(B):Rational design of a metabolic pathway for double cycling of natural substrates leading to autonomous
movement. The activation cycle, starting with glucose and phosphoenolpyruvate, feeds forward the pyruvate−L-
lactate cycle with regeneration of β-NADH, and is controlled by the amount of ATP present in the system. The negative
feedforward regulation by pyruvate enables a tunable continuous local production of oxygen by the motor cycle.
Sufficient concentrations of glucose and PEP as well as positive and negative feedforward mechanisms are crucial for
maintaining a prolonged out-of-equilibrium state.
Nijemeisland et al. (2016), A Compartmentalized Out-of-Equilibrium Enzymatic Reaction Network for Sustained Autonomous Movement, ACS Central Science, 2, 843.
Stromatocytes:
obtained by controlled shape
transformation of polymerosomes, made
from
poly(ethylene glycol)-44-b-
poly(styrene)167 amphiphilic block
cooolymers

Characterization of the nanoreactors

Left: Cryo-transmission electron microscopy (cryo-TEM) image of a nanoreactor .
Middle: TEM image of nanoreactors loaded with the enzymatic network.
Right: TEM coupled with energy dispersive X-ray spectroscopy showing the mapping of sulfur (S), specific to
the cysteines and methionines in the enzymes and their localization inside the nanoreactors .
- Scale bars 100 nm (left) and 1 μm (middle and right).
Nijemeisland et al. (2016), A Compartmentalized Out-of-Equilibrium Enzymatic
Reaction Network for Sustained Autonomous Movement, ACS Central Science, 2, 843.
Nanoreactors movement analysis
(A) Average speeds of the nanoreactors over
time, with 10 mM glucose as starting
concentration. For every time point, average
speeds were calculated from the MSDs of 60
particles over 90 s.
(B) Experimentally determined glucose
concentrations over time.
-The depletion of glucose does not influence
the nanoreactor speed (A).

(C) Average initial speeds (first 90 s) of

nanoreactors loaded with an enzymatic cascade
and fueled with different glucose concentrations.

(D) Average speeds (first 90 s) of nanoreactors

containing enzymatic network at different
glucose concentrations.

(E) Nanoreactor movement in human serum with

the full network compartmentalized.

(F) Motion of nanoreactors loaded with catalase

only; the remainder of the network is added to
the serum.
Nijemeisland et al. (2016), A Compartmentalized Out-of-Equilibrium Enzymatic
Reaction Network for Sustained Autonomous Movement, ACS Central Science, 2, 843.
General design of SMARTS (self-regulated mechanochemical adaptively reconfigurable tunable system)

a, Cross-section
schematic.
b, Threedimensional
schematic.

c, Top-view microscope
images of upright and
bent microfins
corresponding to on
(left) and off (right)
reaction states.

e, Three-dimensional
confocal microscope
image of a hydrogel-
embedded, 18mm-tall
post array immersed in
a bilayer liquid labelled
with fluorescein and
rhodamine B, showing
d, Fortyfive-degree side-view (left) and top-view (right) the interface height to
scanning electron microscope images of 2-mm-wide, be 12 mm.
10mm-long, 18mm-high microfins with the catalyst particles on
tips (inset). He et al. (2012), Synthetic homeostatic materials with chemo-mechano-chemical self-regulation,
Nature, 487,214.
 Homeostasis in SMARTS (self-regulated mechanochemical adaptively reconfigurable tunable system)
via self-regulated chemo-thermomechanical feedback loops
a, Temperature-regulating SMARTS showing a C ↔M
feedback loop: mechanical action of temperature-
responsive gel coupled with an exothermic reaction.

Sideview schematic and top-view microscope images

depict on/off states of the reaction in the top layer.
Exothermic catalytic reactions:

LCST- lower critical solution temperature

*LCST- lower critical solution temperature

b, Temperature oscillations arising from different exothermic reactions driven by
He et al. (2012), Synthetic homeostatic materials with chemo-
temperature-responsive poly(N-isopropylacrylamide) gel. mechano-chemical self-regulation, Nature, 487,214.
 Homeostasis in SMARTS via self-regulated chemo-thermomechanical feedback loops
c, Comparison between temperature oscillations
using hydrogels with different LCSTs:
-32.0 ̊C (poly(N-isopropylacrylamide), black line)
- 27.8 ̊C (poly(N-isopropylacrylamide)
with 5% butyl methacrylatered, red line).

- The control without catalyst did not maintain

temperature and quickly cooled.

d, Time-resolved temperature and vertical

coordinate (z) of microfin tips for the system with
LCST = 27.8 ̊C.
-There is a phase shift between the two curves.
- Inserts show schematic fin configurations.

- This robust selfcontained feedback system,

which is <70 µm thick, regulates T of 0.64cm2
surface for ~6 h (4.20 min per cycle for 95
cycles), with an initial input of only 4.0 µl of
reactants as fuel.
He et al. (2012), Synthetic homeostatic materials with
*LCST: lower critical solution temperature chemo-mechano-chemical self-regulation, Nature, 487,214.
 Temporal Control of Gelation and Polymerization Fronts Driven by an Autocatalytic Enzyme Reaction

Dependence of
the urea–urease
reaction rate on
the pH value

The resultant pH–

time curve over
the coarse of
reaction
Dependence of
the thiol–
acrylate gelation
rate on the pH
value

*Thiocure ETTMP 1300:

a) Reaction of urea and urease (1,2) produces a ethoxylated trimethylolpropane tri(3-
base that drives → mercaptopropionate)
b) thiol–acrylate (3,4) gelation after an induction * PEG diacrylate 700 (PEGDA 700):
period. poly(ethyleneglycol) diacrylate
Jee et al. (2016), Temporal Control of Gelation and Polymerization Fronts Driven by an Autocatalytic Enzyme Reaction, Angewandte Chemie Int . Ed. Engl, 128, 2167.
 Temporal control of thiol–acrylate gelation with the urea–urease reaction

a) Typical pH–time curve with

[urea]0 =0.05M the induction period,
initial pH value after mixing,
0.03M and final pH value indicated. -
Gelation occurred rapidly
0.01M above pH 8.
b) Series of pH–time curves
with decreasing initial urea
conc. [urea]0: induction
period increases.
c) Average final pH value as a
function of the initial
concentrations.

d–f) Induction periods and average initial pH values after mixing.

The fixed initial concentrations were [urea]0= 0.03M, [ETTMP]0= 0.05M, and
[urease]0= 0.5 mg mL-1 (17 units mL-1); ETTMP/PEGDA molar ratio was 2:3; T= 25 ̊C.

Jee et al. (2016), Temporal Control of Gelation and Polymerization Fronts Driven by an
Autocatalytic Enzyme Reaction, Angewandte Chemie Int . Ed. Engl, 128, 2167.
 Frontal polymerization

c) Front speed in
the petri dish as a
function of the
induction period
in a well-stirred
mixture.
Jee et al. (2016), Tempora
Autocatalytic Enzyme Reac

g) Front position
as a function of
time.
black: ascending
fronts
green:descending
fronts

Experiments with a pH indicator (bromothymol blue) in: a–c) a thin layer in a petri dish and d–g) two 4 mL vials with
identical reaction mixtures. Fronts were initiated with NaOH (pH 8).
a) Image taken by shadowgraphy with the position of the polymerization front (dark band) and the pH front (yell. to blue).
b) Intensity profiles along a slice (red line in (a)) in images at three different times and position of the front with time
(circles with a straight-line fit).
d–f) Images of ascending and descending fronts.
Component concentrations: [ETTMP]0= 0.17M, [PEGDA]0= 0.24M, [urease]= 29 units mL-1; T=20 ̊C ; [urea]0= 0.11M (a,b), 0.04–0.27M (c),
0.09M (d).
 Hydrogel degradation
a) Series of images
showing the
return of the thiol–
acrylate gel to the
liquid state
(initial mix. cont.:
[urea]0=0.09m,
[urease]=0.85 mg
mL-1 (29 units mL
mL-1),
[ETTMP]0=0.06M,
[PEGDA]0=0.08M)

b) Dynamic rheology with c,d) Time to return to the liquid state as a function of the urea
storage modulus G’ as a (c) and ETTMP concentrations (d).
function of time. Concentrations of other components: [ETTMP]0=0.1M,
[urea]0=0.03M, [urease]=0.5 mg mL-1 (17 units mL-1);
Jee et al. (2016), Temporal Control of Gelation and Polymerization Fronts Driven by an
Autocatalytic Enzyme Reaction, Angewandte Chemie Int . Ed. Engl, 128, 2167. ETTMP/PEGDA molar ratio was 2:3; T=23 ̊C.
 ‘’Principi dizajniranja ‘’ u Sistemskoj Hemiji:
1) open tvoren sistem (razmena E i m sa okolinom)
2) udaljen od stanja termodinamičke ravnoteže, što
obezbeđuje:
- oblast multistabilnosti
- nestabilno stacionarno stanje
3) nelinearan sistem
4) postojanje mehanizama povratne sprege
- Pozitivne (autokataliza) i/ili negativna
- sprezanje hemijskih reakcija, difuzije, flukseva
naelektrisanja, toplotnih flukseva...
5) kompartmentalizacija
6) kombinatornost
7) samoreplikacija
 „Tehnologija i oruđe“
- nanonauke i nanotehonologije
- supramolekularna hemija
- polimerni materijali...
 tipovi oscilacija:
- proste periodična
- složene oscilacije (mešani modovi)
- aperiodične (haos)
 prostorno-vremenske samoorganizacije
(reakciono-difuzioni sistemi):
- putujući talasi
- embrionalno razviće…
- moždani ritmovi i talasi
(mikroskopska, mezoskopska, makroskopska
koordinacija)
 stvaranju nove adaptibilne,
samoorganizujuće, „pametne“
kompleksne materije, nalik onoj prisutnoj
u živom svetu, koja se u procesima
fizičkohemijske i biološke evolucije
formirala tokom milijardi godina
 Hvala
srdačno na
pažnji!

wladimirmarkowic@gmail.com
vmarkovic@ffh.bg.ac.rs
 Neravnotežna termodinamika
ukupna promena
entropije sistema d iS 
 d eS


dS d iS d eS
  II ZAKON TERMODINAMIKE:
dt dt dt d iS dS
promena entropije usled promena entropije usled 0 0
ireverzibilnih procesa u razmene (energije, materije) dt
sistemu (npr. hemijske sistema sa okolinom
dt
reakcije, difuzija, (fluks entropije); bilo koji sistem
toplotno provođenje) (deS može biti <,>,= 0) sistem

NERAVNOTEŽNA
STACIONARNA STANJA
dS d iS d eS d iS
 0, 0  0
dt dt dt dt samoorganizacija se može odvijati
proizvoljno dugo kada je sistemu
van stanja d iS d i S d eS obezbeđen negativan entropijski
ravnoteže: 0  0 fluks u stanjima udaljenim od
dt dt dt ravnotežnog