50 years bio mimetic supra molecular chemistry hj schneider

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Highlights from 50 Years Biosynthetic Supramolecular Chemistry

Hans-Jörg Schneider

FR Organische Chemie der Universität des Saarlandes , D 66041 Saarbrücken/ Germany

This is a presentation for/from only one hour- so many important contributions had to be neglected

this version has short questions marked Q1 etc on most pages- possible answers are at the end Outline

Some History

Artificial Enzymes

Affinity and Selectivity of supramolecular complexes

Complexation of

Peptides

Nucleotides /Nucleosides

Interference with Biopolymers

DNA/RNA –e.g.a artificial helicase

protein –drug interactions

protein-protein interactions

Nanoparticles binding biomolecules

Molecular Recognition with Microarrays / Chips

Artificial photosynthetic systems / Light energy conversion

Supramolecular chemistry with polymers -Artificial Muscles

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Some History

Emil Fischer. Lock and Key as Enzyme Model 1894

Inclusion Compounds

Paul Pfeiffer Organische Molekülverbindungen 1927

1950- 1975 mostly : principles of enzyme mechanisms / models

Koshland: induced fit : Proc Natl Acad Sci U S A. 1958

Covalent enzyme models e.g. Bruice BBA 1958, 208 Proc. Nat. Acad. Sci. USA 1960

W.P. Jencks, Catalysis in Chemistry and Enzymology, 1989

A.J. Kirby Enzyme Mechanisms, Models, and Mimics Angew. Chem. Int. Ed. Engl. 2003

Warshel et al Chem. Rev. 2006, 3210 (electrostatic origin.... )

Q1a why in these years so few practical applications ?

The begin of supramolecular enzyme models: by Friedrich Cramer :

Q1b why are Cramers papers often forgotten ?

Einschlussverbindungen Review : Angew. Chem. 1952, 437:

( „... es ist uns vor kurzem tatsächlich gelungen, Reaktionen zu finden, die durch Einschlußverbindungen katalysiert werden....“)

Enzym-Modelle Angew. Chem. Int. Ed. Engl. 1962, 434; Tetr. Lett. 1962, 353

Catalysis of Decarboxylation by Cyclodextrins - a Model Reaction for Mechanism of Enzymes. J. Am. Chem. Soc. 1965, 1115

Catalysis of Fission of Pyrophosphates by Cyclodextrin J. Am. Chem. Soc. 1965, 1121 Hans-Jörg Schneider Highlights from 50 Years Biosynthetic Supramolecular Chemistry

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R Breslow, P Campbell - J. Am. Chem. Soc. 1969 ,3805

Regioselectivity change :

o-anisol inside a -CD : Q2b other possible hosts ?

+ HOCl : substitution ratio changes from p:o = 1.5

to 22 with a -CD

Artificial Enzymes :

ML Bender, M Komiyama: Cyclodextrin Chemistry, Reactivity and Structure 1978

(e.g. FM Menger, ML Bender J. Am. Chem. Soc.1966, 131 )

VT D'Souza, ML Bender - Acc. Chem. Res. 1987, 146

R. Breslow , Chem. Rev. 1998,1997; Acc. Chem. Res. 1980, 170

R. Breslow, (Ed.) Artificial Enzymes, 2005

Murakami et al. Chem. Rev. 1996, 721

Hans-Jörg Schneider Highlights from 50 Years Biosynthetic Supramolecular Chemistry

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CH2Br

NaNO2 R-NO2 R-ONO+

Neat 2 : 1

+CP66 6.3 : 1

+ Me4NCl 0.15 : 1

+ Me4NCl has opposite effect : 40-fold change of regioselectivity


Change of Regioselectivity Q3a why? and of Speed Q3b why?

Schneider, Busch Ang Chem 1984

N (CH2)n N

NN (CH2)n

CH2H2C CP66

For most chemical reactions there are no enzymes – Q3a alternatives ?

but supramolecular catalysts

5

C

CCOOEtH

H COOEtCOOEt

COOEt

COOEt

COOEt

e.g. Catalysis of Diels-Alder Reactions by Cyclodextrins (CD)

Breslow et al 1980 f

Schneider et al 1986

without CD: 48 : 1

with CD: 112 : 1

C

CCOOEtH

EtOOC HCOOEt

COOEt

b) Chiral induction 21% Q4c how to improve ?

Rate increase: max. 70

Q4b limitation why ?

with ethylfumarate EF : inhibition

a) Diastereoselectivity increase Q4a why ?


6

Non-covalent interactions as basis: ADH /NADH mimics

Vekemans, Buck (1989) => 95% ee Q5 why ? Kellog ( 1985) =>90 % ee

supramolecular complexes perform not always better

Other NADH analogs ( see e.g. Murakami Chem. Rev: 1996, 721:

Behr and Lehn / Skog and Wennerström / Toda / Engbersen / Murakami / Inoue /Bourguignon / Davies / Gelbard / Iwata / Meyers ….


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Synthetic HydrolasesBreslow, R.; Zhang, B. J. Am. Chem. Soc. 1994, 116, 7893,

(Related hydrolases with cyclophanes : Tabushi, Murakami, Lehn, Diederich….)

220 000-times faster than uncatalyzed / at least 50 turnovers: Q6a what is the drawback ?

Artificial RNAses Breslow etc Q6b why is RNA hydrol faster than of DNA ?

binding group reaction sitesubstrate


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Artificial Nucleases :

E. Kimura ; J. Chin; J. N. Burstyn; R. Krämer; J. Engbersen/ D. N. Reinhoudt, R. Franklin; M. Komiyama, J. R. Morrow, H. Lönnberg; JM Lehn ; HJ Schneider, A.Yatsimirski , T. Bruice, W. Göbel, A. Hamilton …

BNPP as model for DNA , Parathion , Soman, VX etc hydrolysis

M= Eu(III);

BNPP: ko = 2.5 x 10-8 [s-1] at 75°C; t ½ 100.000 hrs

kcat/kuncat = 107 (Schneider et al TL 2002 )

Q7a any practical applications ?

Q7b role of metalion ? of naphthyl units ?

Q7c adanvantage of Ln instead of e.g. Zn ions?

kcat/kuncat = 107 Hegetschweiler et al, Inorg. Chem., 2001,4918

Q7d role of metalion ?


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Alkaline Phosphatase Q8d identify role of the diffent amínoacids E.E.Kim; H.W.Wyckhoff J.Mol.Biol. (1991) 449

N

NH

NH

NH

N

NH

NH

NH

MM

(2) with dinuclear Eu(III)cplx = kdinucl / kmononucl = 70 (BNPP)

plasmid DNA 80% hydrolysis

Q8b why 2 ions?

Schneider et al Angew.Chem 1996, 1219

N

N

N

N

Zn(II)

X HO

(1) Serin protease analogs

–CH2OH : pKa 7.4

Q8a role of metalion ?

Kimura et al

COOH

CONH CH2CH2 N

NH

(3) with simple cofactors

6 fold increase (Eu(III) +plasmid DNA

Q8c how does it work ?

Schneider et al Eur. J. Org. Chem, 2001. 205


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Artificial Restriction Enzymes M. Komiyama J. Biochem. 1995, 665

Q9a the basis of the selectivity ?

Q9b analytical method ?

Q9c adanvantage of Ce instead of e.g. Zn ions?

scission


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Cytochrome P-450 models

C-6 hydroxylation , up to 3000 turnovers ,

with M = Mn, and PhIO

Breslow et al J. Org. Chem. 2002, 67,5057

Q10a drawback of the substrate ?

Q10b which metal ions work ?

Others: Nolte et al. P-450 vesicles

Diederich et al. porphyrin-bridged cyclophanes

Alkene epoxidation

Q10c why so many F ?

Ogoshi et al J. Am. Chem. Soc. 1989, 1912


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2-naphthaldehyde oxidation kcat/KM, = 75 1

also useful for benzoin condensation etc Diederich, et al Angew. Chem. 1986, 1125.

Vitamin B1 Thiamine pyrophosphate TPP analogs

Vitamin B12-functions :

radical rearrangements (methylmalonyl-CoA mutase)

methylation (methionine synthetase)

Murakami et al. Chem. Rev. 1996, 721


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glycine + acetaldehyde => threonine / up to 75 % ee

Breslow et al J. Am. Chem. Soc. 1994, 11234.

Artificial Aldolases etc

Others: transaminations (ß-keto acid => aminoacid , (vitamin B6- dependent aminotransferase)

( eg Kuzuhara, Murakami, Breslow et al )

e-transfer : Vitamin B2 Functions / Flavoenzymes

( e.g Tabushi, DeSouza, Diederich...)


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Cucurbit[7]uril + Ferrocen ( R = -CH2+NMe3 )

G = 90 , TS = -2 ( cf. Biotin-Avidin : G = 90 ) [kJ/mol]

Affinity of Synthetic Receptors – beating Biotin-Avidin (K = 1017 [ M-1])

Q13a practical use of Biotin-Avidin interaction ?

Rekharsky, Kaifer, Isaacs, Gilson, Inoue et al

Proc. Natl. Acad. Sci. USA 2007, 20737

Q13c why is small TS so unusual ?

Whitesides et al Science 1998, 708:

Complexes tripeptide with K = 1017 [ M-1]

Q13b why so high affinity ?


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Selectivity of Synthetic Receptors

OR

ORO X O

Calixarene-crown ethers

best complex: K+/ Na+ selectivity beats valinomycin (X= CH2CH2(OCH2CH2)n, n = 3 or 4, R = alkyl)

(Ungaro, Reinhoudt et al , 1990

1 2 3 4 5 6 7

0

1

2

3

4

5

logK(K+/Na

+)

logKNa

logK

Na

or

logK

(K+ /N

a+ )

logKK

Selectivity-Affinity Correlations

Q14a theor. reason for Selectivity-Affinity Correlation ?

Schneider, Yatsimirsky Chem.Soc.Rev. 2008, 263

18crown6 complexes

less linear correlation of lgK (K+/Na+) vs. lgK(K+)

Q14b why more scatter ?

Q14c why less selective than calix-crown ?


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N

O

N

OO

H

HON

O

O

O

O

O

O

NCH3

NCH3

NCH3

NN

NN

H

HH

Cl-

H

H

+

+

+

Cl-

Cl-

König et al J. Am. Chem. Soc., 2005, 3362 s.also König Chem. Rev. 2006, 106, 3520

Q15a Role of Cu? Why Cu ?

e.g. Gly-Gly-Phe lg K = 4.4

Schneider et al Chem. Comm.. 1999, 907

Q15b which interaction mechanisms ?

Supramolecular receptors für biologically important targets

e.g. Peptides


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Peptide recognition / length and sequencence selective

Ternary complex with MV and peptide

within cucurbit[8]uril Q16a which detection method ?

Q16b other host ?

E. Meghan; N.D. Bouley, A. R. Urbach, J. Am. Chem. Soc., 2005, 127, 14511

Guest K [M-1]Trp-Gly-Gly 1.3×105 Gly-Trp-Gly 2.1×104 Gly-Gly-Trp 3.1×103

N N

NN

H H

O

O

CH2

CH2

8

NN++

Linear adjustable host with

crown for peptide-+NH3- hydrogen bond

+NMe3- for peptide-COO- ion pair

Lipoph group L for side chain group R stacking

Q16c why fluorescence emmision upon complexation?

Q16d which interaction mechanisms ? (see next transparancy)

Q16e performance in other solvents than water ?

Hossain, Schneider J. Am. Chem. Soc., 1998, 11208


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Ion pairing

Stacking

Hydrogen bonding

-+NH3

-COO-

Crown ether

Phe

Dansyl selector group


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Selective Peptide Recognition

Affinity constants K [M -1] in water

0

50

100

150

200

Gly-Gly Gly-Gly-Gly

Gly-Gly-GlyGly

Gly-Phe-Gly

Gly-Gly-Phe

with L = H

Length selectivity

di-, tri-, tetra-

peptides etc

0

5 0 0

1 0 0 0

1 5 0 0

2 0 0 0

2 5 0 0

G l y - G l y -G l y

G l y - G l y -P h e

P h e - G l y -G l y

G l y - P h e -G l y

G l y - T r p -G l y

G l y - A l a -G l y

w i t h L = d a n s y l

S e q u e n c e s e l e c t i v i t y !

o n l y t r i - p e p t i d e s

o n l y g l y - X - g l y

w i t h T r p > P h e > A l a e t c


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NH

NN

NH

N

NN

O

NH

NN

NH

N

NN

O

++

+

+

++

1

I-

I-

I-

I-

I-

I-

K from 5.000 M-1 to 430.000 M-1

Small charge effects:

Adenosin lgK = 4.8, ATP lgK = 4.5

only small nucleobase selectivity

Q19a which mechanism dominates ?

Q19b which measuring method ?

Receptors for Nucleotides / Nucleosides

with amino-cyclodextrins : e.g. ATP K = 106 [ M-1]

Schneider et al , J. Am. Chem. Soc. 1994, 6081; Darcy et al, Perkin Trans 2, 1998 , 805

Menuel, Duval, et al. New J. Chem, 2007, 995 (guanidinium deriv.)

With metal complexes:

Yajima, Maccarrone, et al. Chem. Eur. J. 2003 ,3341

Stacking but controlled by charge

Malojcic, Piantanida, et al.OBC 2005,4373

Aminocyclodextrins for gene delivery /as vector

E. Redenti et al Adv. Drug Deliv. Rev.. 2001, 235

f Alzheimer amyloid cplx J. X. Yu, et al J. Mol. Neuroscience 2002, 51

N+

N

N+

N

M. Sirish, H. J. Schneider, Žinić, Vigneron, Lehn,

J. Am. Chem. Soc. 2000, 122, 5881 Chem. Commun. 1995, 1073


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pyrrole-imidazole hairpins binds to ds-DNA

with subnanomolar affinity

Alkylation of A, mostly in pure A/T tracts, by the electrophilic cyclopropyl residues

Q21 what is the binding mechanism ?

Why so high affinity ?

P.B. Dervan, et al Top. Curr. Chem. 2005 , 1-31


High affinity and selectivity in DNA/ RNA groove binding

Hans-Jörg Schneider

Highlights from 50 Years Biosynthetic Supramolecular Chemistry

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A B C RNA - 5.4 27.5 43 DNA 24 - 6 1

B : a artificial helicase ( Schneider, Wilson et al )

N

HN

N

N

NH

N

H H

H H

N (CH2)n N

H2C CH2

N

N (CH2)n NN

R

R

R

R

R

R R

R

4 Cl

NH2NH

N

NH

NH2

NH

NH2

Gentamicin Spermin

RNA 22.0 40

DNA 1.0 17

Selectivity in polyamine interactionsDiscriminationof RNA vs. DNA

Meltingpoint changes T in [0] at ratio r = 0.3

DNA/ RNA Groove binding, e.g. antibiotics

Q22a: what binding interaction ? Q22b: origin of difference between DNA and RNA ?


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m e l t i n g p o i n t d e c r e a s e e . g . w i t h 6 0 M l i g a n d T = - 3 1 o

w i t h R = H 3 0 M T = - 2 8 o C

R e c o r d h o l d e r s f o r d s D N A d e s t a b i l i z a t i o n

C H 2 N C H 2

C H 2 N C H 2

H

H

R

R

H

H

R

R

H 2 C

H 2 C

NH

C H 2

C H 2 N

H

H

H

H 2 C N C H 2

H 2 C N C H 2

H

H

Cl

Cl

H

HArtificial Helicase

Destabilization of

double-stranded nucleic acids :

stabilize unfolded parts of DNA or RNA

using :

a) phenylderivatives :

will only intercalate into unfolded parts

b) few positive charges in the ligands :

N+ stabilizes double-strands)Schneider et al Angew. Chem., Int. Ed. 1998, 37, 3016



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Interactions with Proteins

Castellano, Diederich Angew. Chem. Int. Ed. 2003, 1210

Zürcher, Diederich J. Org. Chem. 2008, 73, 4345

Alternating cationic (Arg, Lys) and aromatic (Tyr, Phe, Trp) =>

within human growth hormone receptor (hGHR)

Q24b identify all binding contributions

anti-Alzheimer drug E2020 within

active site of acetylcholinesterase

tRNA-guanine transglycosylase (TGT) + nucleobase analogue

Q24a identify all binding contributions


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Interference with Protein–Protein Interactions

Review : Hamilton et al Angew. Chem. Int. Ed. 2005, 4130

e.g. Calixarene derivative bound to cytochrome-c / K= 108 [ M-1] : ion pairing

-chymotrypsin bound to nanoparticle receptor ( ion pairing )

V. M. Rotello et al Proc. Natl. Acad. Sci. USA 2002, 5018.


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Biomolecule-nanoparticle (NP) hybrids

E. Katz , I. Willner, e.g.Angew. Chem., 2004, 6042

A) NP-protein conjugation by electrostatic interactions

B) conjugation adsorption of NPs on natural or

C) synthetic thiol groups of the protein

immobilization Au…SR (Whitesides… )

D) conjugation by use of bioaffinity interactions upon ….streptavidin-biotin binding,

E) or antibody-antigen associations

.


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Molecular Recognition with Microarrays

Nucleic acid hybridization DNA /RNA

– annealing of single strands A. Rich 1960

DNA chips and microarrays for genotyping and expression

DNA-Microarrays Fodor 1980 ff Affymetrix Genechip

Q27a molecular basis of the recognition ?

Q28b what binding strength is expected for GC compared to AT ?

how can it differ ? ( s. Jorgensen J. Am. Chem. Soc. 1990, 2008 )

Protein-Microarrays - protein-protein interactions / Antibody microarrays

Small molecule microarrays (SMMs) - screening of combinatorial libraries MacBeath, Schreiber, Schultz…

38.000 probe spotted oligonucleotide(e.g. 25-mer) microarray

Analysis : Bioinformatics....


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Artificial photosynthetic systems / Light energy conversion

Q28a which structural elements are needed ? Why ? Q28b what are the major challenges ?

Reviews: Balzani et al Chem. Rev. 1996, 96, 759 ; Sauvage et al Chem. Soc. Rev. 1999, 28, 293;

Gust, D.; Moore, T. A.; Moore, A. L. Acc. Chem. Res. 2001,40; Flamigni, Collin,Sauvage, Acc. Chem. Res. 2008, 857 .

porphyrin as photosensitizer

longest lifetime of charge-separated state: 1.6 s (DMF, 163 K) /quantum yield 34%,

(lifetime in bacteriochlorophyll radical cation : ca. 1 s)

Guldi, Imahori et al J. Phys. Chem. A, 2004 , 541

Flamigni, Collin,Sauvage, Acc. Chem. Res. 2008, 857

=> fullerene radical anion

=>ferricenium ion


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Chitosan hydrogel + 10 mM AcOH

950 % volume increase

(a), (b) : Hydrogel expansion

(c), (d) : Hydrogel contraction / e.g. for drug release

uni-directional

Artificial Muscles - Supramolecular chemistry with polymers:

recognition sites in chemomechanical polymers => stimulation by external effector (guest ) compounds

Q29a required properties of the polymer ? how to improve response speed (Q29b) and sensitivity (Q29c) ?

Schneider et al in „Intelligent Materials“ (2008); J. Mat. Chem. (2008);


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Answers to the questions – ( possible answers ! )

Q1a why so few practical applications ? Science in these years was more oriented towards fundamentals and theory

Q1b why are Cramers papers often forgotten ? Cramer changed this field too early ( he became big shot in nucleic acid chemistry )

Q3 – not enough (native )enzymes : alternatives ? a) enzyme mutants; b) catalytic antibodies (drawbacks ?)

always a problem (also for synth enzymes): product binding /saturation- what to do ? remove products , eg in flow reactors

Q3a Change of Regioselectivity why ? The hard oxygen side of the NO2 anions accumulate at N+ centers,

leading to more soft soft-combination /alkylation ( pure speculation !)

Q3b Change of Speed why ? concentration and vicinity effect - the NO2 anions accumulate at N+ centers,

close to guest better (Km) value

Q4a Diastereoselectivity increase why ? Diene and dienophile in restricted orientation inside cavity – which: unpredictable

Q4b Rate increase: max. only 70: why ? Only concentration and vicinity effect (Km value) , no special TS stabilization

Q4c Chiral induction only 21% - how to improve ? Make CD cavity less symmetrical, e.g. by monosubstitution at the rim

Q5a: origin of the stereoselectivity ? Orientation of edcucts by coordination at the Mg, and by stacking and/or C-H hydrogen

bonds

Q6a what is the drawback ? Very special binding groups (Adamantanes) must be there Q6b why is RNA hydrol faster than of DNA ? The 2’-OH group in ribose allows formation of the cyclic intermediate

Q7a any practical applications ? removal of warefare ( biocide agents etc

Q7b role of metalion ? Coordination improves Km, Lewis catalysis + stabilization of phosphate leaving group

of naphthyl units ? stacking improves Km

Q7c adanvantage of Ln instead of e.g. Zn ions? Higher charge density : improves Lewis catalysis + stabilization of phosphate leaving group

Q7d role of metalion ? Coordination improves Km, Lewis catalysis + stabilization of phosphate leaving group

Q8a role of metalion ? Coordination improves Km, Lewis catalysis + stabilization of phosphate leaving group

Q8b why 2 ions? One can act for Lewis catalysis, the other for stabilization of phosphate leaving group

Q8c how does it work ? Both Imidazole and –COOH can help hydrolysis mechanisms

Q8d identify role of the diffent amínoacids The His and Ser can help hydrolysis mechanisms , these +the others can bind metal ions


31

Q9a the basis of the selectivity ? Watson-Crick base pairing

Q9b analytical method ? Sequence analysis by electrophoretic separation, after 32-P labeling autoradiography

Q9c adanvantage of Ce4+ instead of e.g. Zn2+ ions? Higher charge density : improves Lewis catalysis + stabilization of phosphate leaving group

Q10a drawback of the substrate ? Very special binding groups (Adamantanes) must be there

Q10b which metal ions work ? Fe, Mn

Q10c why so many F ? Protect against (self-)oxidation

Q13a practical use of Biotin-Avidin interaction ? Countless- for immobilization of almost everything (e.g. on surfaces- bionanotechnology etc)

Q13b why so high affinity ? Multivalent binding (chelate effect ) mostly hydrogen bonds

Q13c why is small TS so unusual ? Usually strong binding leads to more loss of mobility

Q14a theor. reason for Selectivity-Affinity Correlation ? If G increases also the differences G between two complexes should increase, but see

next

Q14b why more scatter ? Theory 14a only holds if no addtl groups (e.g. substituents at the host) contribute much to the selectivity

Q14c why less selective than calix-crown ? In calix crown the binding space /cavity if more confined

Q15a Role of Cu? Why Cu ? Large coordination sphere of Cu, Cu(II) binds well with Imidazole N

Q15b which interaction mechanisms ? Besides hydrogen bonding to crown stacking of Phe and porphyrin

Q16a which detection method ? Besides NMR : UV (with MV)

Q16b other host ? wide enough cavities with good binding (eg. larger cyclodextrins or cyclophanes)

Q16c why fluorescence emission upon complexation? The quenching by crown oxygen e-lone pairs is removed by complex with –+NH3

Q16d which interaction mechanisms ? hydrogen bonds with crown, ion pairing with COO-, stacking/hydrophobic effect with Phe etc if present

Q16e performance in other solvents than water ? hydrogen bonds AND ion pairing would increase: stronger binding,

but stacking /hydrophobic effect will decrease : less selectivity

Q19a which mechanism dominates ? Stacking / hydrophobic binding

Q19b which measuring method ? UV eg. with porphyrin Soret band…

Q21 what is the binding mechanism ? hydrogen bonds , mostly Hogsteen type

Why so high affinity ? Multivalent binding (chelate effect ) mostly hydrogen bonds


32

Q22a: what binding interaction ? ion pairing with groove phosphates

Q22b: origin of difference between DNA and RNA ? RNA has deeper groove with higher charge density: better binding

Q24a identify all binding contributions Stacking between substrates, hydrogen bonding with aminoacid residues

Q24b identify all binding contributions Mostly cation- - binding

Q27a molecular basis of the recognition ? Hydrogen bonding

Q28b what binding strength is expected for GC compared to AT ?

GC has 3, AT only 2 Watson-Crick hydrogen bonds – thus GC should bind 50% better, but: it differs

how can it differ ?( s. Jorgensen JACS 1990, 2008) secondary electrostatic interactions lower GC ( DAA-AAD….)

Q28a which structural elements are needed ? Why ? Electron donor and acceptor, condcuting spacer, antenna for light absorption

Q28b what are the major challenges ? High quantum yield and long lifetime at ambient temperature

Q29a required properties of the polymer ? Flexibility, shape memory for reversibility, insolubility , mechanic stability

Q29b how to improve response speed? Increase surface to volume of the particle (e.g. micro/nanoparticles, or thin film)

Q29c how to improve sensitivity ? a) increase binding affinity , b) decrease volume of particles: less binding sites

require less guest molecules from the surrounding medium ( compartmentalization effect)-


50 years bio mimetic supra molecular chemistry hj schneider

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