Possibilities of Mesomorphic Order in Polynucleotide Analogues

14 Biomesogens a n d T h e i r M o d e l s : Possibilities of M e s o m o r p h i c O r d e r in P o l y n u c l e o t i d e Analogues

Downloaded by CORNELL UNIV on October 13, 2016 | http://pubs.acs.org Publication Date: June 1, 1978 | doi: 10.1021/bk-1978-0074.ch014

S. HOFFMANN and W. WITKOWSKI Department of Chemistry, Martin Luther University, DDR-40 Halle/S. and Central Institute of Microbiology and Experimental Therapy, Academy of Sciences of the GDR, DDR-69 Jena, East Germany

It seems that life - originated in the fluctuating interfaces of the primordial earth - escaped the threatening a l t e r n a t i v e s of a stiffening death w i t h i n the s t i c k y h i e r a r c h i e s of crystalline order and a senseless end of v a n i s h i n g i n t o the rather infinite fields of fluidity by occupying the s m a l l b o r d e r l i n e s between the kingdoms of order and the surrounding chaos with a m p h i p h i l i c s p e c i e s , fitted to those very housing c o n d i t i o n s , enabled to use and amplify the advantages and to avoid and minimize the traps of this bipartite w o r l d , driven forward between the d i a lectics of excessive statics and dynamics i n t o the d e v e l o p i n g , e n l a r g i n g , o p t i m i z i n g spatial and temporal i n t e r c o n n e c t i v e networks of complicated mesomorphic o r g a n i z a t i o n s . The ancient pool of n e a r l y omnip o t e n t i a l macromolecules - b u i l t up from those amphiphilic moieties - developed i n t o the specializations of i n f o r m a t i v e , f u n c t i o n a l and compartimentive p a r t ners (Figure 1 ) , conserving below the s k i n of t h e i r specific adjustments the continued p r i m i t i v e u n i v e r sality of the origin. Thus, w h i l e a first sudden glance might connect the s t r u c t u r a l features of nucleic acids with i n f o r m a t i o n , those of p r o t e i n s with f u n c t i o n and the remaining c h a r a c t e r i s t i c s of membrane components with compartimentation, a nearer and more d e t a i l e d intimacy with the three dominants of our t o day biopolymeric o r g a n i z a t i o n s seems to reveal much broader ranges of d i f f e r e n t abilities, merging the classical view of i n t e r a c t i n g s t r u c t u r a l i n d i v i d u a l s i n t o the newer aspect of f l u c t u a t i n g mosaics of mut u a l domain cooperativities, where s t e r e o e l e c t r o n i c patterns of interchanging parts of the competitors of the great o l d game anneal i n t o space and time dependent networks of p r e c i s e l y tuned s t e r e o e l e c t r o n i c fits of newly gained u n i t s of complex mesomorphic do0-8412-0419-5/78/47-074-178$12.50/0 © 1978 American Chemical Society Blumstein; Mesomorphic Order in Polymers ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

14.

H O F F M A N N

A N D

wiTKowsKi

Biomesogens and Their Models

179


main

systems. T h i s v i e w a l s o seems to p r o v i d e a b e t t e r under s t a n d i n g f o r an as w e l l b a s i c as c u r i o u s phenomenon, a s p e c i a l c h a r a c t e r i s t i c of biopolyelectrolytic s y s t e m s : the time independent but d i r e c t i o n a l hyste r e s i s , t h a t seems to have g o v e r n e d not o n l y the first i n t e r c h a n g e s i n the p r i m o r d i a l o m n i p o t e n t i a l polyelect r o l y t i c p o o l , but r u l e d , a c c e l e r a t e d and d i r e c t i o n e d t h e d r i v i n g f o r c e s o f i n f o r m a t i o n p r o c e s s i n g s on to the o p t i m i z a t i o n s i n t o the very regions of the central n e r v o u s s y s t e m s of o u r s p e c i e s . The i n c r e a s i n g efforts of the l a s t years i n e l u c i d a t i n g those e f f e c t s are do m i n a t e d m a i n l y by t h e b a s i c i n v e s t i g a t i o n s o f Neumann and K a t c h a l s k y ( 1 - 4 ) « F o l l o w i n g the a c i d - b a s e t i t r a t i o n s t i m u l u s ο t Cox and c o w o r k e r s (5) in the case of rRNA, they d e m o n s t r a t e d the i m p o r t a n c e of generally l o n g - l i v e d m e t a s t a b i l i t i e s and p a r t i c u l a r l y hysteresis phenomena i n b i o p o l y e l e c t r o l y t i c o r g a n i z a t i o n s for b o t h r e g u l a t i o n phenomena and memory i m p r i n t s i n b i o organisms . In t h e i r hands the 2 p o l y ( U ) · p o l y ( A ) triplex a d v a n c e d as a f i r s t s t a r m o d e l n o t o n l y f o r t h e i n v e s t i g a t i o n of h y s t e r e s i s phenomena by spectrophoto m e t r y as w e l l as p o t e n t i o m e t r i c a c i d - b a s e titrations, but a l s o as a f i r s t d e m o n s t r a t i o n o b j e c t f o r inducing l o n g - l i v e d c o n f o r m a t i o n a l changes i n metastable b i o p o l y m e r i c o r g a n i z a t i o n s by e l e c t r i c f i e l d p u l s e s , surprisingly i n the o r d e r of the a c t i o n p o t e n t i a l s of the n e r v o u s membrane (3,4,6). F r o m t h i s a n d f u r t h e r i n v e s t i g a t i o n s a new i n t r i guing dynamic p i c t u r e of b i o s p h e r e emerged, where bio p o l y e l e c t r o l y t i c s y s t e m s , s e n s i t i z e d by t h e i r out s t a n d i n g c h a r a c t e r i s t i c s of e x h i b i t i n g metastabilities and m o l e c u l a r h y s t e r e s e s t o p a s s i v e r é g u l â t i o n s f rom e n v i r o n m e n t a l e l e c t r o m a g n e t i c i n f l u e n c e s and v i c e versa active mediations into self-governed areas, gain the p o s s i b i l i t i e s of elementary cybernetic units with the s p e c i a l f a c i l i t i e s of t ransducer f u n c t i o n s i n gene r a l a n d memory r e c o r d i n g s a n d s t i m u l a t i o n s o f b i o rhythms i n p a r t i c u l a r ( 2 , 7 , 8 ) . The l i s t o f e x a m p l e s and a p p l i c a t i o n s has been e n l a r g e d i n the meantime not o n l y i n the f i e l d of p o l y n u c l e o t i d e s ( 9 - 1 4 ) , but also i n t h e w i d e s p r e a d a r e a s o f p r o t e i n s ( 1 5 - 1 7 ) a n d membrane components (18-23) , thus u n d e r l i n i n g the early p r e d i c t i o n of m e t a s t a b i i i t i e s and m o l e c u l a r hysteresis p h e n o m e n a a s common f e a t u r e s to a l l b i o p o l y e l e c t r o l y tic m o i e t i e s . In these days they cumulated in the i n t e r e s t i n g and i m p o r t a n t r e s u l t s of a f i r s t demons t r a t i o n as a w o r k i n g p r i n c i p l e i n a b i o l o g i c a l p r o c e s s . S c h n e i d e r and c o w o r k e r s (24,25) demonstrated by means o f a s p e c i a l f l o w r e a c t o r t h e f a s c i n a t i n g , but

Blumstein; Mesomorphic Order in Polymers ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

180

M E S O M O R P H I C

ORDER

I N

P O L Y M E R S


y e t somehow e x p e c t e d d e p e n d e n c e o f the a c c u r a c y o f e n z y m i c r e a d i n g a t e m p l a t e f r o m t h e v e r y way o f d o i n g t h i s , thus p r o v i d i n g f o r the f i r s t time evidence for the c a p a b i l i t i e s of h y s t e r e s i s in governing not only the s p a c e , but a l s o the l o n g l y f o r g o t t e n time dependent h i e r a r c h i e s of b i o r e g u l a t i o n s . While these res u l t s s e e m t o o p e n a new f i e l d i n s t u d y i n g chronobiol o g i c a l i n t e r r e l a t i o n s h i p s on t h e l e v e l o f interacting n a t i v e s y s t e m s , o u r own e f f o r t s in this context start e d a n d r e m a i n e d up t o now f a r b e l o w t h o s e l e v e l s of high-ranking ambitions (7,14,26). S t i m u l a t e d by t h e e a r l y e t f o r t s o f Langenbeck ( 2 7 ) t o c r e a t e a n d b u i l d up s o m e s o r t o f biomimetic cTTêmis t ry a t a t i m e when t h e s e a s p e c t s had s c a r c e l y b e e n n o t i c e d , we i n t e n d e d t o s t a r t a p r o g r a m o f m o d e l l i n g c e r t a i n a s p e c t s of the h i t h e r t o yet inaccessible j u n g l e s of n a t i v e b i o p o l y m e r i c i n t e r a c t i o n s . In this c o n t e x t we t r i e d t o a d d f u r t h e r e v i d e n c e f o r molecular h y s t e r e s e s o f some p o l y n u c l e o t i d e t r i p l e x e s (7,12-14), t h a t m i g h t d i s p l a y some r e g u l a t o r y functions in biological viro-, c a n c e r o - and immunemodulations ( 2 8 - 3 2 ) . L o o k i n g f o r the b a s a l f e a t u r e s of b a s e - s t a c k and strand-pattern i n t e r r e l a t i o n s and i n t e r a c t i o n possib i l i t i e s , i t seemed to u s , t h a t the w i d e l y enlarging c h e m i s t r y of t h e r m o t r o p i c mesogens (33) - e s p e c i a l l y in the case of u s i n g h e t e r o c y c l i c reTa*tives ( 3 4 , 3 5 ) o f n u c l e i c a c i d b a s e s as c e n t r a l p a r t s - s h o u l d p r o v i d e r a t h e r g o o d m o d e l s , f i t t i n g some s i m p l e r a s p e c t s of t h e r m o t r o p i c behaviour in the hydrophobic mesomorp h i c core r e g i o n of p o l y n u c l e o t i d e s . Yet the clearly d i s t r i b u t e d m o l e c u l a r mesogen c h a r a c t e r i s t i c s of our s y n t h e t i c l i q u i d c r y s t a l s and t h e i r t h e o r e t i c a l extrap o l a t i o n s i n t o the ordered i n t e r a c t i o n f i e l d s of large e n s e m b l e s do n o t o n l y seem t o o v e r e m p h a s i z e rather s e c o n d a r y and l o g i c a l l y d e l i c a t e s u b c a t e g o r i z a t i o n s ( l y o t ropy and thermot r o p y ) , but might moreover block t h e i r own s c i e n t i f i c d e v e l o p m e n t i n t o t h e cooperative domain systems of mesogen b i o p o l y m e r i c organizations. To b r i d g e t h i s gap b e t w e e n symmet ry i n v i t r o m o d e l s and asymmetrically directed in vivo r e a l i t i e s , it seemed t e m p t i n g , not o n l y to s t u d y p o l y m e r i c mesogens - m a i n l y b u i l t up f r o m c l a s s i c a l m e s o m o r p h i c m o n o mers - as i t has been e x c e l l e n t l y d e m o n s t r a t e d by the groups of B l u m s t e i n , R i n g s d o r f , C s e r , Hardy, Amerik, S t r z e l e c k i , Tanaka a . o . ( 3 6 - 4 6 ) , or to look for mesogen a r e a s even i n t e c h n i c a l p r o d u c t s ( 4 7 ) , but moreover to use s i m p l i f i e d p o t e n t i a l l y mesogenic biop o l y m e r i c systems - "mesogen" here i n the s e n s e of domain c h a r a c t e r i s t i c s rather than in d e s c r i b i n g l a r g e r ensemble areas - for m o d e l l i n g parts of these



14.

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A N D


wiTKOwsKi

181

complex n a t u r a l i n t e r d e p e n d e n c e s . Thus w i t h i n the framework of our i n t e r e s t s i n m e t a s t a b i l i t i e s and hysteresis p h e n o m e n a i n b i o r e g u l a t i o n s , we t r i e d to model n u c l e i c a c i d s from a g r e a t e r d i s t a n c e and to check t h e s e s i m u l a t i o n s i n ( b i o ) p h y s i c a l and b i o l o g i cal i n t e r a c t i o n s t u d i e s . The s o o n e m e r g i n g possibili t i e s f o r p r a c t i c a l a p p l i c a t i o n s t h e n l e d to a more g e n e r a l c o n c e p t i o n o f s t r a n g e n i n g n u c l e i c a c i d s on different l e v e l s of s t e r e o e l e c t r o n i c f i t , utilizing both n a t i v e monotonie s e q u e n c e s and s y n t h e t i c a l monoand o l i g o m e r i c b a s e - p a i r a n a l o g u e s as w e l l as poly m e r i c s t r a n d a n a l o g u e s i n c o m p e t i t i v e and a l i o s t e r i c i n t e r a c t i o n s t u d i e s ( F i g u r e 2 ) . M o d e l l i n g and varying the mesogen domain c o m p o s i t i o n s of n a t i v e s y s t e m s not o n l y by s m a l l n o n m e s o g e n i c a n t i m e t a b o l i t e s b u t also by a t l e a s t p a r t i a l l y m e s o g e n i c a n t i t e m p l a t e s (Figure 3), we h o p e d t o a d j u s t o u r e f f e c t o r s to t h e i r wanted l e v e l s of e f f i c i e n c y r a t h e r t h a n to m i s u s e them f o r a pure jamming of m e t a b o l i c pathways. Materials

and

Methods

Polynucleotides The p o l y n u c l e o t i d e s w e r e comm e r c i a l p r o d u c t s , o b t a i n e d from S e r v a - B i o c h e m i c a and R e a n a l . They have been used w i t h o u t further purifica tion. (A) (3.4/>8S); (U) (>10S); (G) (~10 S ) ; (C) (8-13 S); (I) (10-15 S). Concentrations of p o l y n u c l e o t i d e s in 0.01 M phosphate/ 0.1 M NaCl (PBS/ pH 7 . 2 ) w e r e d e t e r m i n e d s p e c t r o p h o t o m e t r i c a l l y by u s i n g the f o l l o w i n g e x t i n c t i o n c o e f f i c i e n t s : (A)p · £max=l0.000; (U) : £ x=9.430; (G) : S *9.600; (C) : * m a x ° ; ( )n* ^ a x ' ' n

n

n

n

n

n

=

6

1

5

I

m

a

n

s

l

0

4

0

n

mQX

0

CT-DNA C a l f - t h y m u s DNA was a k i n d g i f t of Dr.G.Luck (Central Institute of M i c r o b i o l o g y and Ex p e r i m e n t a l T h e r a p y , A c a d e m y o f S c i e n c e s o f t h e GDR) w i t h a content of 0.28 % of p r o t e i n , s t a b i l i z e d w i t h c h l o r o f o r m . The s t o c k s o l u t i o n was d i l u t e d t o an O D 6 o o f 0 . 6 2 5 by means o f a 0 . 0 0 1 M N a C l s o l u t i o n . 2

Monomeric Thermotropics Long-chained 2-pyridone5 - c a r b o x y l i c e s t e r s were prepared from 2 - p y r i d o n e - 5 c a r b o x y l i c a c i d and the c o r r e s p o n d i n g h a l f e t h e r s of hydroquinone by e s t e r i f i c a t i o n w i t h Ν,Ν -carbonyld i i m i d a z o l e a c c o r d i n g to the S t a a b - p r o c e d u r e (48). D e t a i l e d d e s c r i p t i o n s w i l l be g i v e n e l s e w h e r e JTQ). Long-chained e s t e r s of e n a n t i o m e r i c estradiols and l o n g - c h a i n e d e s t e r - a n i l e s of e n a n t i o m e r i c estro nes w e r e p r e p a r e d by m e t h o d s p r e v i o u s l y described ( 5 0 , 5 1 , 5 3 ) . The e n a n t i o m e r i c e s t r o n e s and e s t r a d i o l s β



182

MESOMORPHIC

ORDER IN

Figure 1. Amphophilic pattern development in nucleic acids, proteins, and membranes

Figure 2. Nucleic acids "strangening' program


POLYMERS

14.

H O F F M A N N

were w i l l

A N D

wiTKOwsKi


p u r c h a s e d from VEB Jenapharm. F u r t h e r be r e p o r t e d e l s e w h e r e (54,55).

183

details


Base-Pair Analogues 2.7-bis - [(dialkylaminoand {oxa}oligoalkylenimino)-acetylamino]-fluo ren-9-ones ("fluoramides" 1-5) w e r e p r e p a r e d v i a the corresponding 2 . 7 - b i s - [(chloroacetyl)-amino]-fluoren-9-one by a procedure described recently (56); see also (57). Vinylmonomers f o r Homo- and C o p o l y m e r i z a t i o n R e actions 1-Vinyluracil, 9-viny1hypoxanthine, and 9 v i n y l a d e n i n e w e r e p r e p a r e d by p r e v i o u s l y described methods ( 5 8 - 6 2 ) , 1 - v i n y l c y t o s i n e by t h e a m m o n o l y s i s of l-vinyl-4-methylthiopyrimidine-2-one (62,63). Polynucleotide Strand-Analogues The following p o l y m e r s ( T a b l e s I and II) w e r e p r e p a r e d by A I B N - o r f-ray induced (Laboratory R a d i a t i o n U n i t R C H - y - 3 0 as a ^OCo-source) p o l y m e r i z a t i o n and copolymerization reactions, respectively, followed in case of (vA, l v O H 3 o . 7 ) n by a p o l y m e r a n a l o g o u s r e a c t i o n . The start i n g amounts of N - v i n y l n u c l e o b a s e s and t h e i r comonomers were a d j u s t e d to y i e l d a n e a r l y 1 : 1 - r a t i o i n the copolymers. Sedimentation Experiments Sedimentation measurements were c a r r i e d out u s i n g a S p i n c o Model E u l tracentrifuge, e q u i p p e d w i t h an u l t r a v i o l e t absorption o p t i c , a monochromator and a p h o t o e l e c t r i c a l s c a n n e r , i n a way p r e v i o u s l y d e s c r i b e d (66). Base-Pairing Experiments Methods employed for b a s e - p a i r c o m p l e x a t i o n have been d e s c r i b e d previously ( 6 2 , 6 4 , 7 3 , 7 4 ) . U l t r a v i o l e t m i x i n g and t h e r m a l profile e x p e r i m e n t s w e r e p e r f o r m e d a c c o r d i n g t o common p r o c e dures ( 7 3 , 7 4 ) . S p e c t r a f o r mixing curves were measur e d w i t h an U n i c a m S P 1 8 0 0 s p e c t r o p h o t o m e t e r (62,64, 7 5 ) * M e l t i n g c u r v e s w e r e run on t h e same s p e c t r o m e t e r , e q u i p p e d w i t h a SP 871 t e m p e r a t u r e program c o n t r ô l e r ( 6 2 , 6 4 , 7 5 ) . ORD s p e c t r a w e r e m a d e o n a 3 a s c o 0R0/UV-5 spectrometer, and the c i r c u l a r d i c h r o i c s p e c t r a were r e c o r d e d on a Gary M o d e l 6 0 s p e c t r o m e t e r , e q u i p p e d w i t h a M o d e l 6 0 0 1 CD a c c e s s o r y (64,75,76). Electron-Microscopic Studies taken at 36.000 · m a g n i f i c a t i o n s i n a c c o r d i n g to procedures p r e v i o u s l y Hysteresis m e a s u r e m e n t s by

Micrographs an E l m i s k o p given ( 6 5 ) «

were IA

Experiments Molecular hysteresis c y c l i c acid-base t i t r a t i o n s of the


184


Table

n

(vU)

n


Table

Induction

I I

(vA,[vC00Na]

0 > 8

(vA,

1

)

3

0

>

7

7

)

2

' W P ]

(vA.IvI]

0

.

0

1

#

9

1

: L

)

8

)

n

n

n

)

( ν Α . [ ν » 3 ι α ]

n

n

ivC0NH ]

(VA, [vPn]

(vC.

n

4

o

(vA,[vOH]

A

(58-61,67-70)

Ura

(58-61,67-70)

X

[vC00Na] " )'

(vA.[vS0 Na] ; )

v

Ade

Copolymers

Copolymer

(

Lit.

Β

AIBN

Β

(vA.

I N P O L Y M E R S

Homopolymers

I

Polymer (vA)

ORDER

0

n

ι

6

)

η

1

>

4

)

[ v œ O N a ]

M

(vC,

[vCX50Na] )'

(vH,

[vCOONa)^

(vH.

tvC00Na]

2

/

) '

:I n d u c t i o n

Β

X

Lit.

AIBN

Ade

COO Ν a

(66,68)

t AIBN

Ade

COON a

(66,68)

Ade

S0 Na

(75)

AIBN

Ade

OH

(65,66)

A I BN

Ade

C0NH

AIBN

Ade

2-pyrrolidone1-yl

AIBN

)

(75)

Ade

4-pyridyl

(75)

Ade

imidazol-l-yl

(75)

AIBN

Ade

3-methyl[(imidazoll-yl) -ium] iodide

(75)

n

n

n

(75)

2

AIBN

n

1 > 1

3

Ï AIBN

Ura

COO Ν a

(67,68)

Cyt

COON a

(69,75)

Cyt

COO Ν a

(62,69)

Hyp

COON a

(62,75)

Hyp

COON a

(69)


14.

H O F F M A N N

A N D


wiTKowsKi

185

triplexes ( Ι ) · ( Α ) · ( Ι ) and ( U ) - ( Α ) · ( I ) were car r i e d o u t as p r e v i o u s l y d e s c r i b e d ( 1 2 - 1 4 , 7 2 ) , u s i n g the t e c h n i q u e s o f Neumann and K a t c h a l s k y ( 1 , 2 , 4 ) . Titra tions were performed in a m o d i f i e d USP-2 spectrometer o f t h e A c a d e m y o f S c i e n c e s o f t h e G D R , w i t h a pH r a n g i n g from 7 . 1 to 3 . 2 5 . η

η

η

n

η

n


DNA-Interaction Measurements ONA i n t e r a c t i o n s w i t h f l u o r a m i d e s w e r e s t u d i e d by D N A - t i t r a t i o n with t h e i n t e r c a l a t o r . M e l t i n g p r o f i l s w e r e o b t a i n e d on U n i c a m S P 1 8 0 0 s p e c t r o p h o t o m e t e r a n d CD s p e c t r a o n a C a r y M o d e l 60 as d e s c r i b e d above u n d e r " b a s e - p a i r i n g s " (21)· Biological Tests The p o l y m e r s w e r e t e s t e d as s i n g l e s t r a n d s i n e u k a r y o t i c and v i r a l p o l y m e r a s e sy s t e m s . In b a s e - p a i r e d c o m p l e x e s w i t h t h e i r mate poly n u c l e o t i d e s they were t e s t e d w i t h regard to antiviral a c t i v i t i e s in establishing a n t i v i r a l states, inducing and p r i m i n g interferon. CT-polymerase Β (DNA-dependent RNA-polymerase) was o b t a i n e d from c a l f - t h y m u s t i s s u e s and a s s a y e d as reported e a r l i e r (71). A c t i v i t y measurements were per formed in a toluene systern, u s i n g a L i q u i d S c i n t i l l a t i o n Counter Mark I ( N u c l e a r Chicago). AMV-Revertase (RNA-dependent DNA-polymerase) was a s s a y e d i n an e n d o g e n o u s A M V - s y s t e m as p r e v i o u s l y de s c r i b e d ( 7 0 ) . A v i a n M y e l o b l a s t o s i s V i r u s was a k i n d g i f t of Dr. J . fiiman (Ins t i t u t e of 0 r g a n i c Chemis t ry and B i o c h e m i s t r y , Ï S A V , Ρ r a h a , C z e c h o s l o v a k i a ) . Measu r e m e n t s we r e p e r f o r m e d w i t h a L K B - W a l l a c e L i q u i d S c i n t i l l a t i o n Counter 81.000. F o r es t i m a t i o n s o f a n t i v i r a l a c t i v i t i e s ( 7 8 ) in g e n e r a l and i n t e r f e ron i n d u e t i o n (62) i n particular, a n i n v i t r o m o u s e L - c e l l s y s tern w a s u s e d . V S V (Vesi cular Stomatitis Virus - s t rain Indiana) - was taken as a c h a l l e n g e v i r u s . Y i e l d s o f i n f e c t i o u s v i r u s were t i t r a t e d by p l a q u e a s s a y on c h i c k e n e m b r y o f i b r o b l a s t s . For interferon ρ riming experiments the e f f e c t s of t h e s e m i p l a s t i e s o n NOV - ( N e w c a s t i e D i s e a s e V i r u s s t rain Hert fordsh ire)-mediated i n t e r f e r o n induction i n m o u s e L - c e l l s was f o l l o w e d b y t h e s a m e common p r o cedures previously described (78). F i r s t o r i e n t a t i n g es t i m a t i o n s o f i n v i v o a n t i v i ral act i v i t i e s of f l u o r a m i d e s were performed i n mice a c c o r d i n g t o common p r o c e d u r e s . F u l l e r d e t a i l s w i l l be given elsewhere (79).


186

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Molecular

Hystereses

in

Polynucleotide

Triplexes

When t h e b e a u t i f u l W a t s o n - C r i c k d u p l e x emerged from a n a m e l e s s mass o f more o r l e s s c o m p l i c a t e d mono-, o l i g o - and p o l y m e r i c s t r u c t u r e s , some l o n g l y missed e s t e t h i c a l f e a t u r e s had been g i v e n back to o r g a n i c chemistry, and t h i s i n both s t a t i c and dynamic a s p e c t s ( 8 0 ) . F i g u r e s 4 , 5 and 6 c o n t r a s t the l e s s c l e a r l y ar ranged peptide backbones of cytochrome c (81), for i n s t a n c e , w i t h the c l e a r l y d i s t r i b u t e d b a s e - s t a c k / s t r a n d - p a t t e r n a r r a n g e m e n t s o f B-DNA and A-DNA o r 1 1 RNA ( 2 8 ) , r e s p e c t i v e l y . W h i l e j u s t the r e d u c t i o n of strancTedness to the b i o l o g i c a l l y p r o m i s i n g duality granted the b i r t h of t h i s s t r u c t u r e , n e a r l y at the same t i m e s u g g e s t i o n s s t a r t e d o r c o n t i n u e d f o r multip l e - s t r a n d e d n e s s i n the b i o l o g i c a l m a t e r i a l s (Figure 7). Four-strands structures, originally a theoreti c a l l y b a s e d p r o p o s a l o f G a v i n ( 9 0 ) , h a v e now b e c o m e a t t r a c t i v e a s p o s s i b l e s t o r a g e f o r m s o f DNA i n the n u c l e o s o m e s o f c h r o m a t i n ( 9 1 ) . Y e t c o n s i d e r a b l y more i n t e r e s t has been s p e n t i n the meantime to triplexes, t h a t had i n f o r m e r time been b e l i e v e d to r e p r e s e n t the common s t r a n d d e s i g n o f DNA a t a l l . F i g u r e 8 r e v e a l s the appearance of the (11) · ( Α ) · ( U ) triplex according to the r e s u l t s of A r n o t t and c o w o r k e r s ( 2 8 ) . The ori g i n a l l y rather theoretical aspects in déâTing with those structure f o u n d a much more r e l i a b l e a n d a t the same t i m e e x c i t i n g b a s i s , when p o l y ( A ) ( 7 , 9 2 ) opened the s t i l l c o n t i n u i n g area of monotonie sequences in DNA a n d RNA i n t e r p l a y s . C o n s e r v e d e v e n a s i t s e e m s in some c a s e s d u r i n g e v o l u t i o n , t h e s e m o n o t o n i e s seem to p l a y a n i m p o r t a n t b u t up t o now n o t y e t elucidated r o l e i n , b i o r e g u l a t i o n s . The t r i p l e x e s , w h i c h might arrange around those t r a c t s in p o l y n u c l e o t i d e s , rem a i n i n g n e v e r t h e l e s s s t r u c t u r e s s t i l l i n want f o r def i n i t e b i o l o g i c a l f u n c t i o n s , and i n the meantime start i n g p o i n t s o r g o a l s of a c o n s i d e r a b l e number of different s u g g e s t i o n s , ranging from a p o s s i b l e importance o f t h o s e s t r u c t u r e i n e a r l y b i n a r y p u r i n e c o d e s on t h e p r i m o r d i a l e a r t h ( 9 3 ) , to the involvement in quite different r e g u l a t i o n s between r e p l i c a t i o n , (reverse) t r a n s c r i p t i o n a n d t r a n s l a t i o n up t o t h e s p e c u l a t i o n s f o r a c t i o n s as c y b e r n e t i c u n i t s ( 1 - 4 , 7 - 1 4 , 2 8 ) o f a hysteretic r e g u l a t i o n c o d e a c t i n g by p h a s e d i r e c t i n g and m a n i p u l â t i n g s t r a t e g i e s i n b i o r e g u l a t i o n s (7). The f i e l d of t r i p l e x s t r u c t u r e s - F i g u r e 9 shows common p a i r i n g s c h e m e s - a n d t h e i r h y s t e r e t i c behaviour, w h i c h had o r i g i n a l l y been the r e s e r v a t e of the working g r o u p s o f Neumann and K a t c h a l s k y ( 1 - 4 ) as w e l l as G u s c h l b a u e r ( 9 - 1 0 ) , became a p l a y g r o u n d of endeavours η

η

n



H O F F M A N N

A N D

wiTKOwsKi


187

Figure 3. Survey of complementary matrix fits in nucleoproteinic systems

Journal of Biological Chemistry

Figure 4. aC-peptide backbone of cytochrome c (81)



188

MESOMORPHIC

Nucleic Acids Research

Figure5. (above) B-DNA (28)

ORDER

IN POLYMERS


Figure 6. (below) 11-RNA (28)


A N D

wiTKOwsKi



H O F F M A N N

Figure 7. Base-hase recognition schemes in polynucleotides



MESOMORPHIC

ORDER IN P O L Y M E R S


Figure 8.

(U) · (A) · (U) -triplex (28) n

Figure 9. Triple-stranded polynucle otide pattern (28). (horn top to bot tom and left to right) U AU, C GC\ CIC\ υ·ΑΊ, I AU, I AI; U'AI/IA-U-pattern in an as yet hypothetical arrangement (94, 95).

n

n

V W Xy"V * Λ - < -


14.

H O F F M A N N

wiTKOwsKi

A N D


from q u i t e d i f f e r e n t p o i n t s o f v i e w ( 7 , 2 8 - 3 2 ) . We h a d been i n t e r e s t e d i n those s t e r e o e l e c t r o n i c p a t t e r n not o n l y g e n e r a l l y because of t h e i r p o s s i b l e involvements in b i o r e g u l a t i o n s , but moreover p a r t i c u l a r l y i n Wat s o n - C r i c k and Hoogsteen r e c o g n i t i o n ambit i o n s of poly(A)-monotonics w i t h r e g a r d to p o l y ( I ) - t r a c t s , due to the v e r y e f f e c t s of the l a t t e r in v i r o - , c a n c e r o - and immunemodulations (7,29-32,62). After looking for a molecular hysteresis in the all-purine ( I ) · ( A ) · ( I ) s y s tern ( 1 3 ) , we s p e n t inter est to the h y p o t h e t i c a l ( U ) - ( Α ) · χ Γ ) triplex (7) e l u c i d a t e d t o g e t h e r w i t h D e C l e r c q and c o w o r k e r s its e x i s t e n c e ( 1 4 , 9 4 , 9 5 ) - F i g u r e 10 shows m e l t i n g p r o f i les a n d ORD c h a r a c t e r i s t i c s - a n d d e m o n s t r a t e d a l s o in t h i s case of a mixed one-pyrimidine/two-purines-trip l e x a m o l e c u l a r h y s t e r e s i s on c y c l i c a c i d - b a s e t i t r a t i o n s . F i g u r e 11 and 12 s u m m a r i z e s o u r e x p e r i m e n t s in c o m p a r i s o n w i t h t h e p i o n e e r i n g s t u d y o f Neumann and K a t c h a l s k y i n c a s e o f ( U ) - ( Α ) · ( U ) . F o r o u r two u n u sual triplex structures the h y s t e r e t i c "lagging be hind" of conformational o r i e n t a t i o n s in t h e i r attempts to f o l l o w the p H - v a r i a t i o n s in the environment seems t o be c a u s e d by s i m i l a r t r a n s c r y s t a l l i s a t i o n between the t r i p l e x and the ( Α ) · ( A ) d u p l e x , as p r o p o s e d by Neumann and K a t c h a l s k y f o r the ( U ) - ( Α ) · ( U ) hys t e r e s i s , e x c e p t t h a t i n o u r c a s e s t h e p r o c e s s s h o u l d be c o m p l i c a t e d i n a s t i l l unknown way by t h e t e n d e n c y to s e l f - a s s o c i a t i o n of p o l y ( I ) ( 1 , 2 , 8 2 , 8 3 ) . W h i l e from here there w i l l a r i s e the n e c e s s i t y to s t u d y those i n t e r r e l a t i o n s h i p s much more t h o r o u g h l y and on a l a r g e r s c a l e , e s p e c i a l l y i n v o l v i n g i n t e r a c t i o n s between nu c l e i c a c i d s , p r o t e i n s and membranes as w e l l as their sensitivity to e f f e c t o r m o i e t i e s and o t h e r environmen tal i n f l u e n c e s , we t r i e d f a r b e l o w t h i s l e v e l t o i n troduce i n t o the p i c t u r e of b i o e f f e c t o r efficiencies ( F i g u r e 3) the above m e n t i o n e d s i m u l a t i o n c o n c e p t s for p r o v i d i n g a n t i m e t a b o l i t e s and a n t i t e m p l a t e s derived from m o d e l l i n g c o n c e p t i o n s in the f i e l d of n u c l e i c a c i d s a n d a d j us t e d f o r m e s o m o p h i c i n t e r a c t i o n s with b i o p o l y m e r i c s y s terns. η

n

n

n


191

η

n

+

η

η

η

+

n

n

n

Modelling

Nucleic

Acids

by

Simple

η

n

Thermotropics

The n i c e l y b a l a n c e d i n t e r p l a y s o f order-disorder f e a t u r e s represented in the a r c h i t e c t u r e of n u c l e i c a c i d s ( F i g u r e 13) ( 8 6 , 8 8 , 9 6 ) , the complex i n t e r g a m e of h y d r o p h o b i c and h y d r o p h i l i c a s p e c t s , of weak and s t r o n g i n t e r a c t i o n s - ranging from the hydrophobic l o n g - c o r e r e g i o n s to the b i z a r r e s t rand c o m p o s i t i o n s with their different f i t s for handling nucleobase ac-


192


ORDER

I N

P O L Y M E R S

30

20

1 0


20

30 -I 30

50

70

90

40

t e m p e r a t u r e {*C )

Figure 10. Thermal hysteresis in the melting profile and ORD-characteristics of (U) - (A) - (I) , the latter in comparison with the arrangement alternatives of the constituents. ORD-spectra: ( ; (U) • (A) · (I) ; ( -) (U) · (A) · (U) ; ( — >) (On ' (A) · (I) ; (- - _) (U) · (A) ; (I) + (A) . n

n

n

n

n

n

n

n

n

n

n

n

n

0.50

Figure 11. Molecular hysteresis in polynucleotide—triplex organizations. Cyclic spectrophotometric acid-base ac 0.40 titrations. Absorbance (A) as a func tion of pH; c = 1.67 10' M triplex, Ο ΙΛ (o 0.625, 0.001M NaCl, pH ~ 7, compared with the melting characteristics of CT-DNA/FA-1 · 2HCI complexation. (3 * 10' M aqueous solution of FA-1 · 2HCI; ratio DNA-phosphate/FA-1 = 1/1). (h) ODcharacteristics of CT-DNA/FA-1 · 2IICI interactions on titration. CT-DNA OD 0.902, O.J M NaCl; other conditions like (a). nn

3

2(;o

Curve

Ratio DNA-P/FA-1 · 2IIC1 1/0.1 1/0.15 1/0.2 1/0.3 1/0.5


MESOMORPHIC

ORDER IN

POLYMERS


212

Figure 30. CPK-illustration of hypothetical intercalative fit of FA-1 into the large groove of DNA. (horn top to bottom) FA-1 approaching the major groove of DNA; intercalative fit from the major groove; the same arrangement from the minor groove (56, 76, 77).


14.

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wiTKowsKi

213



brought back to t h e i r t h e o r e t i c a l s t i m u l u s seems to g a i n a new d i m e n s i o n s f o r m o d e l l i n g h o r m o n e a n d effect o r e f f i c i e n c i e s i n g e n e r a l and i n t e r c a l a t o r effects i n the n u c l e i c a c i d base s t a c k s i n p a r t i c u l a r . It offers a p o s s i b l e e x p l a n a t i o n f o r the v i r o - , canceroand i m m u n e m o d u l a t i v e a c t i v i t i e s of t h o s e compounds in t h e i r a b i l i t y to strangen t h e common n u c l e i c a c i d p a t t e r n of b i o o r g a n i s m and to p r o v o k e both humoral and cellular non-self r e c o g n i t i o n s , w h i l e the o l d V o r l a n der term of " i n f e c t i o n " - r a t h e r unusual in the field of t h e r m o t r o p i c s - f i t s our today b i o l o g i c a l aspects i n a c u r i o u s way, somewhat i n d i c a t i v e and c h a r a c t e r i s t i c f o r the i n h e r e n t connection. M o d e l l i n g and " S t r a n g e n i n g " leotide Strand-Analogues

Nucleic

Acids

by

Polynuc-

Base and s u g a r v a r i a n t s of n u c l e o s i d e s and n u c l e o t i d e s h a v e b e e n d e a l t w i t h i n t h e p a s t i n an a b u n dance, n e a r l y i n c a p a b l e f o r r e v i e w s , monographs or even reference journals (26,121-123). While these var i a n t s of a f i r s t and s e c o n d g e n e r a t i o n o f analogues s t i l l c o n t i n u e a t t r a c t i n g the a t t e n t i o n of people i n t e r e s t e d i n n u c l e i c a c i d chemis t ry and i t s applicat i o n s ( 1 2 3 ) , b e g i n n i n g w i t h the 1960s a t h i r d generat i o n of n u c l e i c a c i d s i m u l a t i o n s emerged from the f l o o d of s t e r e o e l e c t r o n i c i m i t a t i o n s : f a r or l e s s d i s t a n t l y m o d e l l e d s t r a n d a n a l o g u e s r e v e a l e d some import a n c e f o r both t h e o r e t i c a l l y and p r a c t i c a l l y oriented investigations i n the f i e l d of b i o p o l y m e r s and their interaction possibilities (26,58-61,97,124-131). To d e a l o n l y w i t h t h o s e s t r u c t u r e s , modelled from a g r e a t e r d i s t a n c e , there opened f o r s y n t h e t i c a l app r o a c h e s ways of p o l y c o n d e n s a t i o n , p o l y a d d i t i o n freer a d i c a l , photochemical, or ^-ray induced polymerizations or polymeranalogous reactions, possibilities t h a t h a v e b e e n met i n t h e m e a n t i m e by n u m e r o u s synthetic efforts, r e v i e w e d a l r e a d y by d i f f e r e n t authors (26,59,97,128-130,132,133). " As a compromise between the s c r e e n i n g p o s t u l a t i o n s of r a p i d and u n c o m p l i c a t e d a c c e s s to h i g h molec u l a r systems (due to the s e l e c t i o n s of a s i z e criter i o n for i n t e r a c t i o n p o s s i b i l i t i e s of biopolymers within bioregulation hierarchies ( 1 3 4 ) ) by a r o u t e i n d e p e n d e n t f rom t h e n a t u r a l p o l y c o n d e n s a t i o n way (due to a g r e a t e r s u i t a b i l i t y f o r the a l t e r n a t i v e s of matrix polymerizations) and a c e r t a i n degree of stereoe l e c t r o n i c order of our s y n t h e t i e s (due to the desire f o r r e p r o d u c i b i l i t y and f i t of o u r systerns i n their possible interactions with biopolymers) we started



214


from N - v i n y l n u c l e o b a s e s ( 2 6 , 9 7 , 1 2 5 ) , that have also been used by A m e r i c a n and J a p a n e s e g r o u p s (58-61,130, 133). However, d i f f e r i n g from t h e i r g e n e r a l c o n c e p t i o n s , we h a v e t r i e d f r o m t h e b e g i n n i n g t o f i t m i n i m a l l y a l t e r e d b a s e s t a c k s by v a r i a b l e s t r a n d patterns, thus to overcome the o t h e r w i s e obvious l i m i t a t i o n s for useful variations in strand-pattern design (64,135). As model b u i l d i n g p r o v i d e d poly(N-vinylnucleobase-vinylX)-systerns of a l t e r n a t i n g s e q u e n c e and s y n diotactic (isotactic respectively) stereo (isotactic in l . 5 - b a s e s u b s t i t u e n t s ) being capable of polynucleot i d e - l i k e h y d r o g e n - b o n d i n g and b a s e - s t a c k i n g a c t i o n s a t l e a s t o v e r s h o r t e r d i s t a n c e s ( 9 9 , 1 2 5 , 1 3 5 ) , we i n t e n d e d t o f a v o r o u r s y n t h e s i s c o n d i t i o n s IrTto t h e d i r e c t i o n o f t h i s w o r k i n g h y p o t h e s i s . B u t a s we felt o u r s e l v e s u n a b l e to e l u c i d a t e and g r a n t those very c o n d i t i o n s , we h o p e d , t h a t o u r s y s t e m s w o u l d a t least p a r t i a l l y meet o f i n t e n s i o n s h a l f - w a y . As n u c l e o b a s e s in aqueous s o l u t i o n s u s u a l l y e x h i b i t l i m i t e d numbers of r e p e a t i n g p a t t e r n of s t a c k i n g i n t e r a c t i o n s (136, 1 3 7 ) , we s u g g e s t e d t h a t c e r t a i n p r e o r i e n t a t i o n s remaining even under our unfavourable s y n t h e s i s condi t i o n s - c o u l d b u i l d up s t a c k m a t r i c e s , t h a t might p r a c t i c e some s o r t o f s e q u e n c e - and s t e r e o - r e g u l a t i o n . In these context the f o l l o w i n g F i g u r e s 3 1 - 3 6 d i s p l a y in a though i n t r i g u i n g n e v e r t h e l e s s mere hypothetical way o u r hopes and e x p e c t a t i o n s , s t a r t i n g w i t h t h e i n v i t i n g tendencies of v i n y l polymers for h e l i c a l a r rangements ( 1 3 8 , 1 3 9 ) ( F i g u r e 31) over the useful s t a c k i n g a m b i t i o n s of n u c l e o b a s e s , given here for ex ample f o r d i f f e r e n t a d e n i n e s t a c k s ( F i g u r e 32) (135) and one v e r t i c a l i n t e r a c t i o n of a h y p o x a n t h i n e moiety ( F i g u r e 33) ( 1 4 0 ) , to the s p e c u l a t i o n s of v i n y l nucl e o b a s e homo- and c o p o l y m e r i z a t i o n arrangements at the growing-up c h a i n i n the scheme of F i g u r e 3 4 , i l l u s t r a ted further i n case of 9-vinylhypoxanthine-acrylic acid copolymerization (Figures 35 and 36) and e n d i n g w i t h t h e p a r t i a l ( I ) · ( C ) - s i m u l a t i o n as an e x a m p l e for possible biological a c t i v i t i e s (30). Varying both base and s t r a n d c o m p o s i t i o n s , a s p e c t r u m of polymers - i d e a l i z e d w i t h r e g a r d to ratio, s e q u e n c e and s t r u c t u r e f i t i n F i g u r e s 37 and 38 w e r e p r e p a r e d by A I B N - o r j f - r a y i n d u c e d copolymerizat i o n s , f o l l o w e d i n case of (vA, [ ν Ο Η ] ) by a p o l y m e r a n a l o g o u s r e a c t i o n . The s t a r t i n g amounts of N-vi n y l n u c l e o b a s e s and comonomers were a d j u s t e d to yield a n e a r l y 1 : 1 r a t i o i n t h e p o l y m e r s . F i g u r e 39 a d d s for some c h a r a c t e r i s t i c c a s e s t h e r e c e i v e d S - v a l u e d i s t r i b u t i o n s , g i v i n g an i d e a o f t h e m o l e c u l a r w e i g h t d i stributions (66). n

n

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Introduction to Stereochemistry

Figure 31. Helical ambitions of simple vinyl polymers after (138)

Figure 32. Adenine-stacks after (136, 137). (a) RNA; (b) A-DNA; (c) B-DNA; (d) C-DNA; (e) deoxyadenosine-monohydrate and adenosine-S'-phosphate; (f) adenosines'-phosphate; (g) adeninehydrochloride and 9-methyl-adenine-dihydrobromide; (h/k) 9-methtjl-adenine; (i) (A) . n


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Journal of Molecular Biology


Figure 33.

Inosine stacks after (140)

Figure 34. Hypothetical insertion of vinyl comonomers into vinyl nucleobase-stack matrices, bridging gaps between the vinyl groups and allowing a convenient zippingup (26, 64,125,135)

Figure 35. CPK illustration of the speculation given in the precedingfigure,(top) 9Vinijlhypoxanthine/acrylic acid-stack insertion-arrangement; (bottom) built up (vHvCOOH) . n



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Figure 36. CPK illustration of the hypothetical (C)„ · (vH,vCOO~) hybrid compared with the all-poly nucleotide base-paired ( C) · (I )„, vizualizing the hydrogen-bonding and stack similarities between the polynucleotide/mutual strand-analogue hybrid and the polynucleotide duplex (62) n

n

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Figure 37. Idealized schemes of vinyl copolymers with varied nucleohase design (top to bottom and left to right); (vA-vCOONa) ; (vU-vCOONa) ; (vC-vCOONa); (vllvCOONa) (64-71, 75) n

u

n


218



MESOMORPHIC

Figure 38. Idealized schemes of 9-vinykidenine copolymers with varied strand pohrity pattern (top to bottom and left to right); (vA) ; (vA-vCOONa) ; (vA-vS0 Na) ; (vA-vOH) ; (vA-vCONH ) ; (vA-vPn) ; (vA-vP) ; (vA-vI) ; (vA-vm IJ) (64-71, 75) n

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Figure 39. S-value distribution of some characteristic co polymers. ( ) (υΑ, [υΟΗ] . )η; ( ) (vA, [vCOONa] . ) ; (—•—) (υA, [vCOONa] ) ; ( ) (υA, [vP] . ) (66). 0 7

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MESOMORPHIC

ORDER I N P O L Y M E R S

To c h e c k o u r t h o u g h t s as t o t h e p o s s i b i l i t i e s for p o l y n u c l e o t i d e - l i k e mesomophic o r d e r in our synthetic p r o d u c t s , b a s e - p a i r i n g e x p e r i m e n t s w i t h t h e i r mate p o l y n u c l e o t i d e s have been c a r r i e d out i n c l u d i n g the whole set of u s u a l complementary complex formations ( 6 4 , 6 8 , 7 3 , 7 4 , 9 7 ) . The i n v e s t i g a t i o n s - i l l u s t r a t e d by mixing curves, t h e r m a l m e l t i n g p r o f i l e s , and ORD-as w e l l as C D - c h a r a c t e r i s t i c s of F i g u r e s 4 0 and 41 re v e a l that c o o p e r a t i v i t y w i t h i n the " b a s e - p a i r e d com plexes" varies over a rather broad range, reaching the q u a l i t i e s of mutual p o l y n u c l e o t i d e i n t e r a c t i o n s in c a se of the r a t h e r v A - r i c h (vA,[vOH]Q 7) hybridized w i t h the p o o r l y s t r u c t u r e d (U) (141) demonstrated by d e f i n i t e and c o n s i d e r a b l e h y p o c h r o m i s m i n t h e m i xing curves, sharp absorbance temperature p r o f i l e and i n d i v i d u a l l y s h a p e d 0 R D - and C D - s p e c t r a - , and d r o p p i n g down t o t h e l e v e l o f r a t h e r l i m i t e d interactions b y c h a n c e i n c a s e o f t h e n u m e r o u s mo r e p o o r l y fitted analogues in combination with highly ordered, selfa s s o c i a t e d p o l y n u c l e o t i d e s , i n d i c a t e d by low and dif fuse hypoch romism (or even h y p e r c h r o m i s m ) , flat mel t i n g p r o f i l e s and o n l y d i s t u r b e d polynucleotide-ORDa n d C D - s p e c t r a . A s we u p t o now h a v e n o t g o t a n y p o s s i b i l i t y f o r an x - r a y p r o o f o f o u r o r i g i n a l h o p e s and e x p e c t a t i o n s - r e p r e s e n t e d by t h e e a r l y p i c t u r e of F i g u r e 4 2 - we t r i e d t o v i s u a l i z e o n e o f o u r hybrides (of c o u r s e n o t t h e w o r s t o n e ) a t l e a s t by electron m i c r o s c o p y as a s u b s t i t u t e ( 6 5 ) , and h e r e t h e overall shape s i m u l a t i o n s between the " n a t i v e " 2 ( ϋ ) · ( Α ) and the s e m i p l a s t i c 2 ( U ) - ( v A , f v O H ] 7 ) n seems to add fur t h e r e v i d e n c e f o r s t r u c t u r a l s i m i l a r i t i e s and a c c o m p l i s h e s comparable r e s u l t s of the P i t h a group (130) in the f i e l d of homopolymers (Figure 43). e

n


n

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n

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0 #

F r o m a l l o f t h i s t h e c o n c l u s i o n s m i g h t be d r a w n very carefully, that our hypothesis works best if at a l l - i n the p o l y m e r i z a t i o n of h i g h l y s t a c k i n g v i n y l n u c l e o b a s e s , f a v o r i n g perhaps at l e a s t in these c a s e s some s o r t o f c o m b i n e d s t e r e o - and s e q u e n c e re g u l a t i o n by s e l f - o r g a n i z e d s t a c k m a t r i c e s , and o r d e r i n g the e x p e c t e d j u n g l e of sequence and stereoirreg u l a r i t i e s ( a t p r e s e n t we h a v e n e i t h e r really convin c i n g i n d i c a t i o n s for the p r e f e r ence of the expected sequence a l t e r n a t i o n nor f o r the l e s s f a v o r a b l e but p o s s i b l e a l t e r n a t i v e of block polymer formation) at least p a r t i a l l y for short i n t e r p l a y s of monotonie se quences of p o l y n u c l e o t i d e s with l i m i t e d recognition t r a c t s of our s y n t h e t i c s - a l l o w i n g the c u r i o u s games of a c q u a i n t a n c e s between l a t e d e r i v a t i v e s of evolu t i o n a r y o p t i m i z a t i o n s and p a t t e r n , both r e l a t i v e s of ancestors of e a r l y n u c l e i c acids ambition in nature


Blumstein; Mesomorphic Order in Polymers ACS Symposium Series; American Chemical Society: Washington, DC, 1978. 50

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260 260 255 250 248 250 252

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and c r e a t i o n s o f l a t e n u c l e i c a c i d a m b i t i o n s i n o u r brains · T h o u g h a l l t h e s e h y p o t h e s e s h a v e t o be l o o k e d u p o n w i t h c a u t i o n , s i n c e we c a n o n l y s u p p l y indirect e v i d e n c e in f a v o r of i t , a c c o r d i n g to the i n d i c a t i o n s from these b a s e - p a i r i n g e x p e r i m e n t s , our s y n t h e t i c po l y m e r s seem to r e v e a l b o t h s t r u c t u r a l and f u n c t i o n a l s i m i l a r i t i e s w i t h t h e i r p o l y n u c l e o t i d e s t a n d a r d s . Thus one might hope o r s p e c u l a t e , t h a t a f t e r a p e r i o d of necessary s t e r e o e l e c t r o n i c optimizations - their "na t i v e " i d e a l s "was t e d " y e t a b o u t f i v e m i l l i a r d y e a r s f o r i t , a n d t h i s t h o u g h we h a v e n o t g o t t i m e e n o u g h to f o l l o w t h e s e t r a c e s s h o u l d be t a k e n a s an e x c u s e in f a v o r o f us - t h e y m i g h t i n f u r t h e r future appear use f u l as a n t i t e m p l a t e s i n b i o r e g u l a t i o n s . A t p r e s e n t our r a t h e r i n s u f f i c i e n t l y f i t t e d s t r a n d s d e p e n d i n g on t h e i r base and s t r a n d - p o l a r i t y c o m p o s i t i o n s exhibit ef f e c t s i n i n v i t ro c a l f - t h y m u s p o l y m e r a s e Β ( D N A - d e pendent RNA-polymerase) ( 7 1 , 1 3 5 ) and AMV-revertase (RNA-dependent DNA-polymerase) assays (70,142) (Figu res 44 and 4 5 ) , the s t i m u l a t o r y and i n h i b i t o r y a c t i v i t i e s i n the e u k a r y o t i c and the v i r a l p o l y m e r a s e sys tems b e i n g i n t r i g u i n g l y s l i g h t l y c o u n t e r - c u r r e n t with r e g a r d to the m o l e c u l a r s t rand d e s i g n . The antitemplat e e f f e c t s , t h a t seem t o be m a i n l y a r e f l e c t i o n o f the interhybrid r e c o g n i t i o n s r a t h e r t h a n an e x p r e s s i o n of the p r o b a b l y l e s s pronounced p l a s t i c - p r o t e i n i n t e r a c t i o n s , a r e c o m p l e t e d by t h e a s s i s t a n t r o l e o f t h e p o lymer s t rands i n i n d u c i n g ant i v i r a l p r o t e c t i o n in mouse L - c e l l s when b a s e - p a i r e d w i t h t h e i r mate polyn u c l e o t i d e s . W h i l e p a r t i a l 2 ( U ) * ( A ) - and 2(I) -(A) analogues only succeeded in e s t a b l i s h i n g a s l i g h t an t i v i r a l s t a t u s , the l a t t e r i n a d d i t i o n demons t r a t i n g some p r i m i n g e f f e c t s ( F i g u r e 46) ( 7 8 , 1 4 3 ) , partial ( Ι ) · ( C ) - s i m u l a t i o n s l i k e t h e i r famous a l l - p o l y n u c leotide ideal induce interferon, the i n t e r f e r o n induct i o n b y t h e ( C ) · ( v H , v C O O N a )' r e p r e s e n t i n g the first example gained with a d r a s t i c a l l y a l t e r e d (I) -component (Figures 36 and 47) (62). n

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These b i o l o g i c a l experiments confirm s i m i l a r re s u l t s of o t h e r groups ( 5 9 , 1 3 3 ) - m a i n l y i n the field of h o m o p o l y m e r i c p l a s t i c s - and i l l u s t r a t e the possib i l i t i e s of our today p o l y n u c l e o t i d e - l i k e mesogens to model and s i m u l a t e even at t h e i r p r e s e n t s t a g e s of s t e r e o e l e c t r o n i c i n s u f f i c i e n c i e s rather complex b i o p o l y m e r i n t e r a c t i o n . Thus i n o u r eyes i t seems a l i t t l e b i t e n c o u r a g i n g , that not o n l y the base-over c r o w d e d homopolymers but a l s o the more p o o r l y basef i t t e d c o p o l y m e r s - w h i c h d i s p l a y on t h e o t h e r hand developing f a c i l i t i e s of a d j u s t i n g t h e i r variable


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10

c o n c e n t r a t i o n (mol/1


Figure 44. Effects of some polynucleotide strand analogues on the transcription of CT-DNA by DNA-dependent RNΑ-polymerase (B) in vitro (71): Assay: pH 7.9; 0.1M Tris-HCl; 2 mU Mn ; 0.1 mM DTT; 0.02 mM BTPs; P-ATP and -OTP; H-ATP and -OTP; 8-10 y DNA; Τ = 37°C. (vA, [vOH] , ) ; (vA, [vCONH ] ) ; (vA, [vPn] . ) ; (vA, [vP] ) ; (vA, [νΙ] ) ; (vA, [vm IJ] . ) ; (vU, [vCOONa] ) like control without definite effect. 2+

32

3

0 7

n

2

nj)

n

1Λ η

iJf

1A

n

3

0 8

n

0 6

n

f

n




Figure 45. Effects of some polynucleotide strand analogues in an in vitro AMVrevertase assay (RNA-dependent DNA polymerase; endogenous template-primer com bination) (70). Assay: pH 8.0; 50 mM Tris-HCl; 2 mM DTT; 5 mM Mg ; 1 mM Mn ; 50 mM NaCl; 0.2 mM dBTPs; 10 /*C H-TTP; Τ = 37°C. 2+

3


2+

MESOMORPHIC

ORDER I N P O L Y M E R S

25600 -


12 800 E

6400

c ο

3200-

I

1600

Β c

800.

Ζ

400-

c

200100-

I

il

III

IV

V

VI

VII

Figure 46. Effects of preincubation of mouse L-cetts with poly nucleotide triplexes and their partial analogues on subsequent inter feron induction by NDV and on VSV propagation (78, 143). Assays: 10 txg/ml DEAE-dextran; Τ = 37°C; pH 7.2; PBS; concentration of the complexes 10' M (sum of bases), (a) Interferon priming: ( ) control; (—·—) priming only with ΌΕΑΕ-dextran; (WÊÊË ) 3 hr-treatment without DEAE-dextran; ( H i ) 3 hr-treatment with DEAE-dextran; (\ I) 24 hr-treatment with DEAE-dextran. (b) Antiviral states (c = VSV-test, c = VSV control). 4

0

ϊ II III IV V VI VII

Complex

VSV-yield log PFU [c/e ]

(vA, [νΟΗ] . ) · 2(U) (υA, [vCOONa] . ) · 2(U) (vA, [vOH] . ) • 2(I) (vA, [vCOONa] ) · 2(1) (vH,vCOONa) · 2(AL (A) · 2(U) (A) · 2(I)

^07 -0.6 -0.5 -1.0 -0.7 -0.8 -0.5

0

η 7 η

n

0 8

0 7

n

n

n

n

n

n

0

n

n

H

n

n


14.

H O F F M A N N


A N D WITKOWSKI

101

[A]

poly(l) · poly(vqvCOONa] ) OD 248 2


0.7

U

jLr/

229

COONa NH

poly(C) · poly(vH,vCO0Na)

2

O D

COONa

poly(vH,vC00Na)'

' r poty(vC,[vœONa] î'

ΛΑ):

30

2

complex

50

cone.

VSV-yield

[M]

logPFU[y

(SU m of bases) antiviral state

-k

poly( 1 ) · poly(vC£vCOONa] )' 3 -10 2

poly(C) · poly(vH,vCOONa)'

250

0.6

ι.3·ιο"

4

70

90

['Cl

interferon ind.

- 0.8

- 0.6

-1.4

-2.0


Figure 47. Establishment of antiviral states and interferon induction by partial (I) * (C) -simulations in a mouse L-cell system; interferon induction by (C) · (I) : —S.5 log PFU [c/c ] for comparison. Other conditions of assaying like Figure 46 (62). n

n

n

0


n

230



s t r a n d d e s i g n at l e a s t to a c e r t a i n degree to wanted l e v e l s of e f f i c i e n c y - r e v e a l a c t i v i t é s , which might be r e g a r d e d ( a s s i s t e d by t h e r e s u l t s o f t h e M e r t e s group (133) of b l o c k i n g d e f i n e d p r o t e i n s ) not o n l y in terms ot the mentioned o b s t r u c t i o n of m e t a b o l i c p a t h ways by u n s p e c i f i c i n t e r a c t i o n s , b u t p e r h a p s as early beginnings of a biomesogen s i m u l a t i o n chemistry, trying t o r e a c h t h e g o a l s o f n a t i v e b i o p o l y m e r s and by t h i s , d e v e l o p i n g t h e i r mesogen a s p e c t s from the u n d i r e c t i o n e d games o f l a r g e e n s e m b l e s o f r a t h e r "unint e l l i g e n t " i n d i v i d u a l s to the d i r e c t i o n e d domain c o o p é r â t i v i t i e s of " i n t e l l i g e n t " s t e r e o e l e c t r o n i c units. Final

Remarks

Yet at t h i s point the q u e s t i o n remains nevertheless without any d e f i n i t e a n s w e r , if there is any sense i n m o d e l l i n g the h i g h l y evolved b i o p o l y m e r i c mes o g e n s o f o u r t o d a y l i f e by d u l l and a t t h i s s t a g e of refinement o v e r s i m p l i f i e d a n a l o g u e s , w i t h the presumption of using those s i m u l a t i o n s a f t e r a t h i n k a b l e p r o c e s s of refinement and a d j u s t m e n t for assisting and even i m p r o v i n g o p t i m i z e d p a t t e r n of n a t u r a l efficiency. It i s p a r t of the q u e s t i o n w e t h e r man-made s t e r e o e l e c t r o n i c p a t t e r n c o u l d a c t not o n l y as c o m p e t i t o r s , b u t m i g h t a d v a n c e for s u b s t i t u t e s a n d partners of the n a t i v e s of the great process.

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P O L Y M E R S

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December 8,

1977.


Possibilities of Mesomorphic Order in Polynucleotide Analogues

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