T H E O R E T I C A L C O N F O R M A T I O N A L A N A L Y S I S

O F C Y C L I C O C T A D E P S I P E P T I D E S

V. Z . P l e t n e v a n d E . P . P o p o v UDC 615.779.90

The investigation of the spatial s t ruc tu re of cycl ic depsipeptides with r egu la r ly a l ternatIng a - a m i n o and hydroxy-ac id res idues is of in teres t in connection with the i r biological act ivi ty and, in pa r t i cu la r , with the specif ic influence on the t r anspor t of ions through cell and mitochondrial membranes [1, 2]. P rev ious ly , by means of a theore t ica l analysis , the conformational possibi l i t ies of a s e r i e s of di- [3, 4], t e t r a - [5, 6], hexa- [7], and dodecadepsipeptides [8] containing respec t ive ly , 6, 12, 18, and 36 atoms in the r ing were studied, and the geomet r i c and thermodynamic p a r a m e t e r s of the opt imum fo rms were determined. For these compounds, the most p r e f e r r e d spatial fo rms were found and the s ta tes of the conformat ional equUib- r i um in polar and nonpolar media were deduced. The conformations of a number of methyl e s t e r s of N - a c e t y l - a - a m i n o acids and of methylamides of O - a c e t y l - ~ - h y d r o x y acids were also calculated [9], and the same applies to a number of more complex l inear depsipeptides [10] modeling f ragments of the cycl ic compounds mentioned above. The investigation of the s t e reochemica l in teract ions between the c loses t mem- bers of the depsipeptide chain pe rmi t t ed the select ion of a set of opt imum forms descr ibing the conforma- tional s tates of the s imples t l i nea r depsipeptides. It was shown that the canonical fo rms found for these compounds can be cons idered as a conformational code in the analysis of the s t ruc tu re of more complex compounds. The resu l t s of a calculat ion of conformat ions [3-8] agree well with the exper imenta l resu l t s obtained by the ORD, NMR, IR, dipole moment, and x - r a y s t ruc tura l analyt ical methods [4, 8, 11, 12].

The presen t paper gives the resu l t s of a theore t ica l study of the conformational s tates of cycl ic N- methylated octadepsipeptides consist ing of eight regu la r ly a l ternat ing L - a - a m i n o and D - a - h y d r o x y acid

res idues (24 atoms in the ring). Some compounds of this s e r i e s , such as [ (L- MeVal- D- HyIv)~ ] ,* show a high ant imicrobia l act ivi ty and a capaci ty fo r binding a lka l i -meta l ions [11.

As the model fo r calculat ion we se lec ted the cyclooctadepsipept ide [ (L-MeAla-D-Lac)~ ] with methyl groups on the C a a toms. In the se r i e s of cycl ic octadepsipept ides , this molecule pos se s se s the g rea tes t conformational f r eedom (with the exception of der ivat ives having Gly and Glyco res idues) . As follows f r o m previous work [9], the introduction of more voluminous side chains does not lead to quali tat ively new con- format ions of the main chain but, in the main, affects only the values of the thermodynamic p a r a m e t e r s , i .e . , the posit ion of the equi l ibr ium of the opt imum fo rms . The approach to the analysis of the spatial s t ruc tu re of the cyclooctadepsipept ides , the procedure for calculation, the values of the bond lengths and valence an- gles , and the potential functions of the a t o m - a t o m interact ions used in the p resen t investigation were s imi - l a r to those which we have descr ibed in the analogous study of the cyclohexadepsipept ides [7].

The formula of the cyclooctadepsipept ide cons idered is shown in Fig. 1. The calculat ion of the opti- mum conformat ions of the molecule was pe r fo rmed by minimizing the potential energy, taking into account the nonvalent in teract ions of the a toms, the e lec t ros ta t i c in teract ions , and the tors ional energy.

*HyIv, Lac, and Glyco a re the symbols used for r e s idues of ~ -hydroxy i sova le r i c , lact ic , and glycolic acids .

M. M. Shemyak[n Institute of the Chemis t ry of Natural Compounds, Academy of Sciences of the USSR. Trans la ted f r o m Khimiya Pr i rodnykh Soedinenii, No. 2, pp. 220-224, March-AprU, 1973. Original a r t ic le submit ted June 22, 1972.

©1975 Consultants Bureau, a division of Plenum Publishing Corporation, 227 West 17th Street, New York, N. Y. 10011. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, microfilming, recording or otherwise, without written permission of the publisher. A copy of this article is available from the publisher for $15.00.

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TABLE i. Optimum Conformations of [(L-bleAla-D-Lac)4 ]

Conformations Angle, deg I

1 2 I 3 4 5 6 7 8 i

(I~ 1 gr 1 O~

~9 a

Ot W~ O~ W5 O~

¢7 W7 Os Ws

299 93 69

333 289 21 7o

27:~ 17

291 269 22

259 145

259 234 249 [

14 71

,349 277 233 238 223 264

62 257 231

263 265 229 2?8 240 240 258 97 338 244

7 54 66 85

318 49 327 125 23 116 77 55

281 27 318 295 138 30 265 60 38 295

129 81

326 279 I

i: 53

273 I 16

253 25

2531 288

119 124 29

106 236 228 245 160 353 112 78

340 313 122 349 81

280 234 235 176 115 135 63

221 259 56

102 313 258 352 245 162

112 87 41

261 345 26 65

175 106 33 75

318 311 167 232 195

9 10

114 321 128 268 122 263 131 320 110 268 20 279 69 249

349 254 269 235

19 87

3~0 256 57

162 281

25 105 83

257 71 80

155

F(D) 6,8 8,9 5,5 9,1 8,4 7,7 11,8 10,6 10,9 12,4

Unv 3,4 0 7, 3,4 4,7 7,3 11,1 14,8 13,3 22,6 Uel 1,5 3,8 0 4,0 1,8 0,I 0,S 1,0 5,~ 3,6 (E = 4) Uto r O 1,6 1, 1,5 1,4 2,0 2,2 1,7 1,8 2,3

5,1 3,0 3,7

8,6 0,5 0

1,5 4,5 6,3

,2

0,9

7,9 9,2

10.4

0 3,3 5,1

12,3 12,6 13,7

~=1 U t o t ¢ ~ 4

~=10

30,1 16,0 14,3

12,7 4,0 3,4

31,1 23,6 23,2

No te s . The v a l u e s of the a n g l e s of r o t a t i o n @i and ~ i w i th odd i n d i c e s we a s c r i b e to the h y d r o x y - a c i d r e s i d u e s and t h o s e w i th even i nd i ce s to the a m i n o a c i d r e s i d u e s ; in o r d e r to c o m p a r e the r e s u l t s o b t a i n e d wi th t h o s e of p r e c e d i n g in - v e s t i g a t i o n s , the a n g l e s have b e e n r e p r e s e n t e d by the 1966 n o t a t i o n [14]; the r e l a t i v e v a l u e s of the t o t a l e n e r g y and of the ind iv idua l e n e r g y c o n t r i b u t i o n s a r e g iven in k c a l / m o l e .

0

0

,~: N C'

H ~ CH a CH 3 l) 1

. . . . J

Fig, 1. Structural formula of the cyclic

octadepsipeptide [iCM;;i;-D:[ac), l • The mutua l p o s i t i o n s of the bonds in the f r a g - m e n t i l l u s t r a t e d c o r r e s p o n d to the v a l u e s

¢~ ='~ =0.

s uming tha t the f o r m s of [(L-MeAla-D - L a ~ ]

The s e a r c h fo r the l o c a l m i n i m a was p e r f o r m e d by v a r y i n g the 14 a n g l e s of r o t a t i o n ¢ i ( C a - N and C c~ - O ' ) and g i(C ~ - C ' ) , w h i c h w e r e s e l e c t e d as i ndependen t v a r i a b l e s (two a n - g l e s dependen t ) .

The in i t i a l nul l a p p r o x i m a t i o n s f o r m i n i m i z a t i o n w e r e s e l e c t e d on the b a s i s of the c o n f o r m a t i o n a l c h a r t s of l i n e a r

c o m p o u n d s m o d e l i n g the f r a g m e n t s [ i L - M e A l a - D - h a c ~ ], n a m e l y , the me thy l e s t e r of N - a c e t y l - N - m e t h y l - L - a l a n i n e ( A c - L - M e A l a - O M e , 1) and the d i m e t h y l a m i d e of O - a c e t y l - D -

l a c t i c a c i d ( A c - D - L a c - N M e 2 , II). The m a p s of compounds (I} and (II), w h i c h a r e shown in F i g . 2, f o r m a s e t of e q u i p o - t e n t i a l s e c t i o n s (0, 1, 2, 3, 5, and 10 k c a l / m o l e ) ; t hey w e r e o b t a i n e d by v a r y i n g the ang l e s of r o t a t i o n ¢ (C a - N o r C a - O') and ,I, (C ¢x - C ' ) by i n t e r v a l s of 20 ° and c a l c u l a t i n g the non- v a l e n t i n t e r a c t i o n s of the a t o m s [9]. As can be s e e n f r o m F i g . 2, c o m p o u n d (1) p o s s e s s e s c o n s i d e r a b l y g r e a t e r c o n f o r - m a t i o n a l p o s s i b i l i t i e s than (TI). This g i v e s g r o u n d s f o r a s -

w i th s m a l l e n e r g i e s of the nonva len t i n t e r a c t i o n s [n a l l the l o c a l s e c t i o n s of the r i n g a r e d e t e r m i n e d p r i m a r i l y b y the c o n f o r m a t i o n a l s t a t e s of the f r a g m e n t s con ta in ing the h y d r o x y - a c i d r e s i d u e s . At the s e l e c t e d v a l u e s of the ang l e s ¢ and ~I, of. the h y d r o x y - a c i d r e s i d u e s (they a r e l o c a t e d m a i n l y in the r e g i o n of the m i n i m u m of P) , the f u l f i l l m e n t of the cond i t ion f o r r i n g c l o s u r e is e n - s u r e d by a v a r i a t i o n in the a n g l e s ¢ and ~I, of the a m i n o a c i d r e s i d u e s wi th in the l i m i t s of the fou r a p p r o x i - m a t e l y e q u i v a l e n t l o w - e n e r g y r e g i o n s on the m a p of compound (1) - R, B, L , and P . Wi th such an a p p r o a c h ,

212

210

r 6

i 18o ~o 3oo ~oo o

r ~c 8~'Iv)

,R j \ . . /

I

Fig. 2. Conformat ional cha r t s of the methyl e s t e r of N - a c e t y l - N - m e t h y l - L - a l a n i n e {Ac-L-MeAla-OMe) (I} and of the d imethyl - amide of O - a c e t y l - D - l a c t i c acid {Ac-D-Lac-NMe2} (II).

the amino acid res idues fulfill the role of pecul ia r hinges with a l imi ted f r e e d o m of rotat ion. Fixing the angles ~ and ~, of the four hydroxy-ac id r e s idues l a r g e l y p r e d e t e r m i n e s the region of pe rmi t t ed values for all the pa i r s ¢ , ~I, of the amino -ac id r e s i d u e s , i .e. , the i r quadrants on the oonformat ional char t of (1).

As the initial approx imat ions for the s e a r c h for the op t imum conformat ions we took s t r u c t u r e s in which the p a r a m e t e r s ¢ and ~I, of not l e s s than two hydroxy-ae id r e s idues were p r e sen t in the map of c o m - pound (12) in the mos t ene rge t i ca l ly favorable region P. A total of ten null approx imat ions mos t favorab le f r o m the point of view of the c loses t in teract ions and ensur ing the fo rmat ion of a c losed s y s t e m were taken for minimizat ion.

Table 1 gives the values of the potential ene rgy (Utot) , the dipole moments (p), and the values of the

angles ¢ and ~I, of the op t imum conformat ions of [(/.-MeAla-D-Lac)4 ] with t r a n s - a m i d e and t r a n s - e s t e r groups and a lso contr ibut ions to Uto t of the ene rgy of nonvalent in teract ions (Unv) , of the to rs iona l ene rgy (Utor) , and of the e l e c t ro s t a t i c in teract ions (Uel }. The values of Uel were ca lcula ted at th ree values of the effect ive d ie lec t r ic constant , ee f f = 1, 4, and 10. The change in Uto t due to the different contr ibut ions of the ene rgy Uel may show a tendency to a shift of the conformat ional equi l ib r ium on pass ing f r o m an iner t to a

po la r med ium [7, 13]. The f igures in the table show that fo r the compound [(L-MeAla-D-Lac)4 ] the mos t favorab le a re the f i r s t two f o r m s , N 1 and N 2.

A c h a r a c t e r i s t i c fea ture of the N 1 conformat ion is that the p a r a m e t e r s • and ,I, of all the hydroxy-ao id res idues a re in the mos t favorab le region f r o m the point of view of nonvalent in te rac t ions , P . The carbonyl groups of the amino- and hydroxy-ac id res idues in this f o r m have the opposite pseudoaxial or ien ta t ions with r e spec t to the mean plane of the r ing. The side groups occupy the pseudoequator ia l posi t ions .

In the N 2 f o r m {apparently p r e f e r r e d in a po la r medium}, two hydroxy-ac id r e s idues a r e p r e sen t in the P s ta te and two in the L s ta te . St ructure N 2 p o s s e s s e s a somewhat e longated el l ipsoidal fo rm. The e a r - bonyl groups of the th i rd and seventh hydroxy-ac id res idues a re d i rec ted to opposi te s ides of the plane of the r ing as c o m p a r e d with the eight r emain ing C =O groups; the carbonyl groups of all the r e s idues a r e in- cl ined in some degree or o ther f r o m the pseudoaxial or ienta t ion towards the cen te r of the molecule . The side chains , deviating in pa i r s in different d i rec t ions , occupy an in te rmedia te posi t ion between the pseudo- axial and pseudoequator ia l or ienta t ions . The p re fe ren t i a l nature of this conformat ion as c o m p a r e d with the N 1 conformat ion is due mainly to the nonvalent in teract ions of the a toms of the different r e s idues . The en- e r g y dif ference of the N1 and N 2 f o r m s , taking into account the contr ibutions of Unv and Utor, is 1.8 k c a l / mole . However, the advantage of the N 1 s t ruc tu re in re la t ion to Uel {~Uel =2.3 k c a l / m o l e at Cef f =4) makes it the mos t probable one in a nonpolar medium.

If the assumpt ions adopted in the calcula t ion [7] a re taken into account, then in a fu r the r cons idera t ion and exper imen ta l invest igat ion of the spat ia l s t r u c t u r e s of the eyolooctadepsipept ides the N 3 - N 5 c o n f o r m a - t ions cannot be comple te ly ignored. The rea l iza t ion of the o ther op t imum f o r m s (N6-N10} is e x t r e m e l y un- l ikely.

213

L I T E R A T U R E C I T E D

1. lV[. M. Shemyakin, Yu. A. Ovchinnikov, V. T. Ivanov, V. K. Antonov, E. I. Vinogradova, A. M. Shkrob, G. G. Malenkov, A. V. Evstratov, I. D. Ryabova, I. A. Laine, and E. I . Melnik, J. Membr. Biolog., 1, 402 (1969}.

2. M.M. Shemyakin, V. K. Antonov, L. D. Bergelson, V. T. Ivanov, G. G. Malenkov, Yu. A. Ovehinnikov, and A. M. Shkrob, The Molecular Basis of Membrane Function, Prentice-Hall, Englewood Cliffs, New Jersey (1969}.

3. E .M. Popov, V. Z. Pletnev, G. M. Lipkind, and S. F. Arkhipova, Izv. Akad. Nauk SSSR, Ser.Khim., 33 (1971).

4. E .M. Popov, V. Z. Pletnev, S. L. Portnova, V. T. Ivanov, P. V. Kostetskii, and Yu. A. Ovchinnikov, Zh. Obshch. Khim., 4._~1,420 (1971).

5. V.Z. Pletnev and E. M. Popov, Izv. Akad. Nauk SSSR, Set. Khim., 991 (1970}. 6. E .M. Popov and V. Z. Pletnev, Biofizika, 16, 407 (1971}. 7. E .M. Popov, V. Z. Pletnev, A. V. Evstratov, V. T. Ivanov, and Yu. A. Ovchinnikov, Khim. Prirodn.

Soedin., 616 (1970). 8. V.T. Ivanov, I. A. Laine, N. D. Abdullaev, V. Z. Pletnev, G. M. Lipkind, S. F. Arkhipova, L. B. Senya-

vina, E. N. Meshcheryakova, E. M. Popov, V. F. Bystrov, and Yu. A. Ovchinnikov, Khim. Prirodn. Soedin., 221 (1971}.

9. E .M. Popov, G. M. Lipkind, V. Z. Pletnev, and S. F. Arkhipova, Khim. Prirodn. Soedin., 184 (1971}. 10. E .M. Popov, V. Z. Pletnev, G. M. Lipkind, and S. F. Arkhipova, Khim. Prirodn. Soedin., 191 (1971). 11. J. Konnert and I. L. Karle, J. Amer. Chem. Soc., 91, 4888 (1969}. 12. Yu. A. Ovchinnikov, V. T. Ivanov, A. V. Evstratov, V. F. Bystrov, N. D. Abdullaev, E. M. Popov, G.

M. Lipkind, S. F. Arkhipova, E. S. Efremov, and M. M. Shemyakin, Biochem. Biophys. Res. Commun., 3_77, 668 (1969}.

13. G.M. Lipkind, S. F. Arkhipova, and E. M. Popov, Zh. Strukt. Khim., 11, 121 (1970). 14. J . T . Edsal, P. J. Flory, J. C. Kendrew, A. M. Liquori, G. Nemethy, G. N. Ramachandran, and H. A.

Scheraga, J. Mol. Biol., 1_.55,339 (1966); Biopolymers, 4_..~, 121 (1966); J. Biol. Chem., 241, 1004 (1966}.

214