Molecular Mechanics of Cyclopropane Peptide Analogs of Aspartame

Chapter 12

Molecular Mechanics of Cyclopropane Analogs of Aspartame

Peptide

Implications for Three-Dimensional Requirements of the Sweet Taste Receptor

Downloaded by IOWA STATE UNIV on April 13, 2017 | http://pubs.acs.org Publication Date: December 31, 1991 | doi: 10.1021/bk-1991-0450.ch012

E. Will Taylor, Susanne Wilson, Charles H . Stammer Department of Medicinal Chemistry and School of Chemical Sciences, University of Georgia, Athens, G A 30602

Molecular mechanics calculations on conformationally restricted cyclopropane peptide analogs of aspartame were used to develop a model for their binding to the sweet taste receptor, in which the ester alkyl group of the active analogs (aspartyl-1-aminocyclopropane carboxylic acid esters, Asp-Acc-OR) binds to the same site as the phenyl group of aspartame. The two possibilities for the active conformation correspond to the Temussi and Goodman models for the sweet taste receptor. The conformational restrictions imposed by incorporating isomers of 2,3-methanophenylalanine or 2,3-methanoproline into aspartame analogs are shown to be incompatible with either of these models, explaining their lack of sweet taste.

I n r e c e n t y e a r s , s i g n i f i c a n t p r o g r e s s has been made i n o u r u n d e r s t a n d i n g o f t h e s t e r e o c h e m i c a l b a s i s o f sweet t a s t e . In p a r t i c u l a r , t h e h y p o t h e s i s o f S h a l l e n b e r g e r and A c r e e ( I ) r e g a r d i n g t h e i m p o r t a n c e o f a d j a c e n t hydrogen bond donor and a c c e p t o r groups ( t h e "AH + B" m o i e t y ) has g a i n e d wide a c c e p t a n c e and has been a p p l i e d by v a r i o u s a u t h o r s ( e . g . 2-8). However, t h e r e i s a l a c k o f c o n s e n s u s (6-8) r e g a r d i n g t h e a c t i v e c o n f o r m a t i o n o f t h e p e p t i d e sweetener aspartame (L-Asp-L-Phe-OMe) and, by i m p l i c a t i o n , t h e t h r e e - d i m e n s i o n a l shape o f t h e sweet t a s t e r e c e p t o r r e c o g n i t i o n s i t e . The r o o t o f t h i s p r o b l e m i s t h e c o n f o r m a t i o n a l f l e x i b i l t y o f p e p t i d e t a s t a n t s l i k e aspartame and many o f i t s a n a l o g s , which p r e c l u d e s a u n i q u e and o b v i o u s h y p o t h e s i s f o r t h e a c t i v e c o n f o r m a t i o n . Thus, i n o r d e r t o d e v e l o p a t h r e e - d i m e n s i o n a l r e c e p t o r m o d e l , t h e c o n f o r m a t i o n a l p r o p e r t i e s o f a number o f d i f f e r e n t a n a l o g s must be studied. Most u s e f u l i n t h i s r e g a r d a r e c o n f o r m a t i o n a l l y r e s t r i c t e d o r r i g i d a n a l o g s , which by t h e i r a c t i v i t y o r i n a c t i v i t y c a n s u p p o r t o r i n v a l i d a t e a h y p o t h e t i c a l r e c e p t o r model. T h i s a p p r o a c h has been u s e d by T e m u s s i and c o l l a b o r a t o r s (5-6), who have r e c e n t l y c h o s e n r e l a t i v e l y r i g i d n o n - p e p t i d e t a s t a n t s t o s u p p o r t t h e i r model o f t h e a c t i v e c o n f o r m a t i o n o f aspartame, and by Goodman and c o l l a b o r a t o r s 0097-6156/91/0450-0162$06.00/0 © 1991 American Chemical Society

Walters et al.; Sweeteners ACS Symposium Series; American Chemical Society: Washington, DC, 1991.


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( 7 ) , who have u s e d s t e r i c a l l y r e s t r i c t e d p e p t i d e and r e t r o p e p t i d e a n a l o g s t o d e v e l o p a somewhat d i f f e r e n t r e c e p t o r model. One approach t o c o n f o r m a t i o n a l c o n t r o l i n p e p t i d e a n a l o g s i s t h e u s e o f h i g h l y c o n s t r a i n e d amino a c i d s , i n w h i c h s u b s t i t u t i o n s r e s t r i c t t h e phi-psi ( φ - φ ) space t o s m a l l , well defined regions of t h e Ramachandran p l o t . In p a r t i c u l a r , a, a - d i s u b s t i t u t e d amino a c i d s ( 9 ) , such as t h e w e l l s t u d i e d o r - a m i n o i s o b u t y r i c a c i d ( A i b ) , a r e r e s t r i c t e d t o about 1% o f t h e Ramachandran map, compared t o o v e r 15% f o r most amino a c i d s , and 50% f o r g l y c i n e (10). A d d i t i o n a l c o n s t r a i n t i s i n t r o d u c e d when t h e a, a - d i s u b s t i t u e n t s a r e b r i d g e d t o f o r m a c y c l o a l k a n e system, t h e s i m p l e s t examples b e i n g t h e 2,3-methano amino a c i d s (2,3-MeAA), p e r h a p s b e t t e r known as t h e " c y c l o p r o p a n e amino a c i d s " , of which 1 - a m i n o c y c l o p r o p a n e c a r b o x y l i c a c i d (Acc) i s t h e p a r e n t compound (11). I n t h i s p a p e r , we r e p o r t on t h e c o n f o r m a t i o n a l a n a l y s i s o f v a r i o u s a s p a r t y l c y c l o p r o p a n e amino a c i d e s t e r s , t h e t a s t e p r o p e r t i e s o f w h i c h have been r e p o r t e d p r e v i o u s l y (12-14). Of t h e s e , o n l y t h e p a r e n t compounds (Asp-Acc-OR) a r e sweet (12), whereas a l l f o u r i s o mers o f Asp-2,3-MePhe-OMe a r e t a s t e l e s s (13), and Asp-2,3-MePro-OR analogs are b i t t e r (14). Based on m o l e c u l a r mechanics c a l c u l a t i o n s , v a l i d a t e d by c o m p a r i s o n s w i t h X - r a y c r y s t a l s t r u c t u r e s where p o s s i b l e , we w i l l p r o p o s e p r o b a b l e modes o f b i n d i n g f o r t h e a c t i v e compounds t o t h e sweet t a s t e r e c e p t o r . These r e s u l t s w i l l be i n t e r p r e t e d i n t h e l i g h t o f p u b l i s h e d r e c e p t o r models, i n p a r t i c u l a r , t h e Temussi and Goodman models ( 5 - 7 ) . S e v e r a l o t h e r p u b l i s h e d models o f t h e a c t i v e c o n f o r m a t i o n s o f a s p a r tame were n o t c o n s i d e r e d as t h e y have have r e c e n t l y been shown t o have poor p r e d i c t i v e v a l u e (8). Methods f o r t h e m o l e c u l a r mechanics s t u d i e s C o m p u t e r - m o d e l l e d s t r u c t u r e s o f t h e Acc d e r i v a t i v e s and a s p a r t a m e were b u i l t u s i n g t h e s t a n d a r d m o l e c u l a r m o d e l i n g o p t i o n s o f t h e SYBYL program ( T r i p o s A s s o c . , S t . L o u i s ) , and t h e c o n f o r m a t i o n a l e n e r g e t i c s were e v a l u a t e d u s i n g i t s SEARCH o p t i o n . Low e n e r g y c o n f o r m e r s were d e t e r m i n e d by m o l e c u l a r m e c h a n i c s c a l c u l a t i o n s , u s i n g t h e T r i p o s f o r c e f i e l d (15), s u p p l e m e n t e d w i t h some a d d i t i o n a l parameters f o r t h e c y c l o p r o p a n e system d e r i v e d from experimental data. F o l l o w i n g A l l i n g e r ' s a p p r o a c h i n t h e MM2 force f i e l d (17), a s p e c i a l atom t y p e was d e f i n e d f o r t h e c y c l o p r o p a n e carbons. A l l parameters and f o r c e c o n s t a n t s i n v o l v i n g t h e c y c l o p r o pane c a r b o n atom t y p e were t a k e n t o be t h e same as t h o s e i n v o l v i n g sp3 c a r b o n ( t h e SYBYL C.3 atom t y p e ) , e x c e p t f o r one t o r s i o n a l param e t e r ( d e s c r i b e d below) and t h e f o l l o w i n g a l t e r e d e q u i l i b r i u m bond l e n g t h s and a n g l e s : c y c l o p r o p a n e C-C b o n d l e n g t h s o f 1.50 Â and i n t e r n a l C-C-C a n g l e s o f 6 0 ° . In o p t i m i z e d s t r u c t u r e s , t h e s e parameters resulted in v a l u e s o f about 118.5° f o r t h e e x o c y c l i c H-C-H a n g l e s and t h e N-C -C2 a n g l e o f Acc (sometimes c a l l e d t h e τ a n g l e ) . A l l o f t h e s e a r e r e a s o n a b l y c l o s e t o e x p e r i m e n t a l v a l u e s as r e v i e w e d by Barone e t a l . (16). In a d d i t i o n t o a l l o w i n g a more e x a c t r e p l i c a t i o n o f e x p e r i m e n t a l bond l e n g t h s and a n g l e s o f t h e c y c l o p r o p a n e r i n g , u s e o f t h e s p e c i a l c y c l o p r o p a n e c a r b o n atom t y p e p e r m i t s t h e i n c o r p o r a t i o n o f a unique V t o r s i o n a l term f o r the 0=C-C -N t o r s i o n a l a n g l e ( p s i ) o f Acc ( p e r i o d i c i t y -2, b a r r i e r 4.4 k c a l / m o l e ) . T h i s a d d i t i o n t o t h e f o r c e f i e l d , f i r s t u s e d by B a r o n e e t a l . i n a a

2

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m o d i f i e d MM2 c a l c u l a t i o n (16), r e p r o d u c e s t h e s t a b i l i z a t i o n o f c o n f o r m a t i o n s i n w h i c h a v e c t o r t h r o u g h t h e c a r b o n y l C=0 bond b i s e c t s t h e c y c l o p r o p a n e r i n g ( i . e . p s i = 0° o r 1 8 0 ° ) w h i c h i s o b s e r v e d e x p e r i m e n t a l l y i n m i c r o w a v e s p e c t r a (18) and c r y s t a l s t r u c t u r e s (12,19) and p r e d i c t e d by ab initio quantum m e c h a n i c s c a l c u l a t i o n s (16). The r e c e n t c o m p a r a t i v e s t u d y by B a r o n e e t a l . (16) demon s t r a t e s t h a t s t a n d a r d f o r c e f i e l d s l a c k i n g such a t o r s i o n a l t e r m f a i l to reproduce t h i s c o n f o r m a t i o n a l e f f e c t , which i s e l e c t r o n i c i n o r i g i n and i s due t o t h e π c h a r a c t e r o f t h e c y c l o p r o p a n e r i n g system. T h e p a r a m e t e r we h a v e u s e d f o r t h i s V torsional barrier (4.4 k c a l / m o l e ) i s from a microwave study o f c y c l o p r o p a n e c a r b o x a l d e h y d e (18).


2

F o r t h e c o u l o m b i c p o t e n t i a l e n e r g y term, t h e d i s t a n t - d e p e n d e n t d i e l e c t r i c model was used (the d e f a u l t o p t i o n i n SYBYL), and c h a r g e s f o r t h e n e u t r a l p r o t e c t e d amino a c i d a n a l o g s were c a l c u l a t e d by t h e G a s t e i g e r - M a r s i l i method (20), which, u n l i k e s e m i - e m p i r i c a l quantum mechanics methods such as MNDO, i s independent o f c o n f o r m a t i o n , and t h u s does not b i a s t h e c o n f o r m a t i o n a l s e a r c h i n f a v o r o f t h e c o n f o r m a t i o n upon w h i c h t h e i n i t i a l c h a r g e c a l c u l a t i o n was performed. However, t h e p r e f e r r e d c o n f o r m a t i o n s and r e l a t i v e e n e r g i e s o f v a r i o u s c o n f o r m a t i o n s o f t h e s e compounds were found t o be f a i r l y independent of e l e c t r o s t a t i c s , i . e . a p p r o x i m a t e l y t h e same r e s u l t s were o b t a i n e d i f t h e c o u l o m b i c term was o m i t t e d from t h e c a l c u l a t i o n s . G r i d s e a r c h (which i n v o l v e s a r i g i d r o t o r approach) was u s e d t o c a l c u l a t e t h e t o t a l s t e r i c energy of t h e Acc d e r i v a t i v e s o v e r t h e e n t i r e phi-psi s p a c e , u s i n g 5 o r 10 d e g r e e a n g l e i n c r e m e n t s . The r e s u l t i n g d a t a f i l e s were c o n t o u r e d w i t h r e s p e c t t o e n e r g y and p l o t t e d as phi-psi plots. However, i t s h o u l d be p o i n t e d out t h a t i n o u r graphs t h e a n g l e s a r e p l o t t e d from 0° t o 360°, r a t h e r t h a n from -180° t o 180°, t h e c o n v e n t i o n f o r t r a d i t i o n a l Ramachandran p l o t s . V a l i d a t i o n of the force f i e l d l i s h e d experimental data

model f o r Acc

by

comparison

with

pub

The e n e r g y - c o n t o u r e d m o d i f i e d Ramachandran p l o t f o r t h e model p e p t i d e o f t h e p a r e n t compound, i . e . N-acetyl-Acc-N-methylamide, i s shown i n F i g u r e 1, and t h e minimum energy c o n f o r m a t i o n o f t h e p r o t e c t e d Acc, i n d i c a t e d on F i g u r e 1 by X a t phi = 280° and psi = 0 ° , i s shown i n F i g u r e 2A. The minimum a t (80°, 0°) i s e s s e n t i a l l y i s o e n e r g e t i c t o t h e g l o b a l minimum i n d i c a t e d by X. O v e r a l l , our phi-psi map f o r t h i s compound i s r a t h e r s i m i l a r t o t h a t o b t a i n e d by B a r o n e e t al. u s i n g AMBER (16), e x c e p t t h a t our c a l c u l a t i o n s r e p r o d u c e t h e psi minima a t 0° and 180° o b s e r v e d e x p e r i m e n t a l l y , due t o our i n c o r p o r a t i o n o f t h e V t o r s i o n a l term d i s c u s s e d p r e v i o u s l y . A s i m i l a r map was c a l c u l a t e d by V a r u g h e s e e t a l . (21), b u t a g a i n i n c o r r e c t minima f o r psi were p r e d i c t e d due t o l a c k o f t h i s t o r s i o n a l term. The f o r c e f i e l d model i s f u r t h e r v a l i d a t e d by t h e c r y s t a l s t r u c t u r e o f A s p - A c c - O P r (12) ( F i g u r e 2B). The c o n f o r m a t i o n o f t h e Acc p o r t i o n o f t h i s m o l e c u l e i n t h e s o l i d s t a t e i s v i r t u a l l y i d e n t i c a l t o t h e g l o b a l minimum energy c o n f o r m a t i o n o f t h e p r o t e c t e d Acc model p e p t i d e ( F i g u r e 2A) . The two m o l e c u l e s a r e shown superimposed i n F i g u r e 2C. Furthermore, a r e c e n t s u r v e y o f c r y s t a l s t r u c t u r e s c o n t a i n i n g t h e A c c m o i e t y (19) shows t h a t , compared t o c a l c u l a t i o n s done w i t h s t a n d a r d f o r c e f i e l d s ( e . g . 16,21) t h e minima p r e d i c t e d by our f o r c e f i e l d model c o r r e l a t e e x c e p t i o n a l l y w e l l with the observed s t r u c t u r e s . 2



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0

ΪΘ0

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ψ

Figure 1. Phi-psi plot for the protected A c c model peptide (structure shown i n Figure 2 A ) . Energy above the global minimum (indicated by X ) is contoured i n 1 kcal/mole increments, up to 7 kcal/mole. The local minima for psi = 180° are about 3.5 kcal/mole above the global m i n i m u m . Several common types of peptide structure are indicated as follows: a: 3io Helix; b: α Helix; c: Type I β turn.


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Figure 2A-2B. Stereoviews of structures of: A : The global m i n i m u m energy conformation of the A c c model peptide; B: The X-ray structure (12) of the sweet peptide analog aspartyl A c c propyl ester.


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C

Figure 2C-2D. Stereoviews of structure of: C : Overlap of 2A (dashed lines) and 2B (solid lines), showing that the A c c conformations are virtually identical; D: The calculated global minimum energy conformation of the peptide sweetener aspartame.


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B a s e d on t h e s e c a l c u l a t i o n s , i t a p p e a r s t h a t t h e most o p t i m a l h e l i c a l c o n f o r m a t i o n f o r Acc i n p e p t i d e s i s t h e 3^Q h e l i x ( a , F i g u r e 1), a l t h o u g h a h e l i c e s (b, F i g u r e 1) and l e f t - h a n d e d h e l i c e s a r e a l s o w i t h i n 3 o r 4 k c a l / m o l e o f t h e minimum. Most i n t r i g u i n g i s t h e o b s e r v a t i o n t h a t Acc r e s i d u e s would be v e r y e f f e c t i v e i n s t a b i l i z i n g a t y p e I β t u r n ( c F i g u r e 1 ) , w h i c h t o o u r knowledge has n o t y e t been e x p l o i t e d i n p e p t i d e drug d e s i g n . However, i t has r e c e n t l y been shown e x p e r i m e n t a l l y t h a t t r i - and t e t r a - A c c p e p t i d e s f o l d into d i s t o r t e d t y p e I β t u r n s and 3 h e l i c e s (11), f u r t h e r v a l i d a t i n g t h e c o m p u t a t i o n a l m o d e l , s i n c e t h e s e a r e t h e two c l a s s i c a l secondary s t r u c t u r a l t y p e s t h a t a r e c l o s e s t t o t h e c a l c u l a t e d g l o b a l minimum. f

1 0


C o n f o r m a t i o n a l p r e f e r e n c e s o f t h e Acc r e s i d u e i n Asp-Ace e s t e r s A l t h o u g h t h e f o r e g o i n g demonstrates t h e c o r r e s p o n d e n c e between t h i s f o r c e f i e l d model f o r Acc d e r i v a t i v e s and v a r i o u s e x p e r i m e n t a l o b s e r v a t i o n s , t h e Acc p e p t i d e used t o d e r i v e F i g u r e 1 i s not t h e b e s t model f o r t h e compounds o f i n t e r e s t , which a r e e s t e r s o f Asp-Acc. The e n e r g y - c o n t o u r e d m o d i f i e d R a m a c h a n d r a n p l o t p r o d u c e d by r o t a t i o n s a b o u t phi and psi i n t h e A c c r e s i d u e o f A s p - A c c - O P r i s shown i n F i g u r e 3. I t i s a p p a r e n t t h a t t h e l o c a l minima f o r psi = 180° a r e s u b s t a n t i a l l y l o w e r f o r e s t e r s t h a n t h e y a r e f o r a m i d e s ( F i g u r e 1 ) , b e i n g i n f a c t i s o e n e r g e t i c t o t h e c o n f o r m a t i o n s w i t h psi - 0°. T h i s i s due t o t h e f a c t t h a t , i n t h e amides, t h e r e a r e s u b s t a n t i a l s t e r i c i n t e r a c t i o n s between t h e c y c l o p r o p a n e r i n g p r o t o n s and t h e C - t e r m i n a l amide p r o t o n when t h e amide bond i s o v e r t h e r i n g (psi - 180°). In t h e e s t e r s , t h e r e i s no s u b s t i t u e n t e q u i v a l e n t t o t h e amide p r o t o n on t h e e s t e r oxygen, so t h e s t e r i c i n t e r a c t i o n i s r e d u c e d r e l a t i v e t o t h e amides when psi - 180°. The i n t e r a c t i o n s o f t h e e s t e r oxygen l o n e p a i r s were t a k e n i n t o account i n t h e c a l c u l a t i o n o f F i g u r e 3 by d e f i n i n g a s p e c i a l atom t y p e w i t h MM2 t y p e l o n e p a i r parameters ( 2 7 ) ; t h i s was n e c e s s a r y s i n c e SYBYL f o r c e f i e l d c a l c u l a t i o n s i g n o r e i n t e r a c t i o n s o f t h e d e f a u l t l o n e p a i r atom t y p e . F i g u r e 3 i n d i c a t e s t h a t f o r a l l p r a c t i c a l purposes t h e r e are o n l y f o u r p o s s i b l e c o n f o r m a t i o n s o f t h e Acc r e s i d u e i n t h e Asp-Acc-OR analogs. The two minima f o r phi a r e c a . ± 8 0 ° , and f o r psi e i t h e r 0° or 180°. The 4 p o s s i b i l i t i e s a r e i n d i c a t e d by a - d i n F i g u r e 3. C o n s i d e r a t i o n s o f which o f t h e s e f o u r c o n f o r m a t i o n s b e s t o v e r l a p w i t h t h e p o s s i b l e a c t i v e conformations of aspartame s h o u l d h e l p suggest which one might be t h e a c t u a l a c t i v e c o n f o r m a t i o n . C o n f o r m a t i o n a l p r e f e r e n c e s o f t h e A s p a r t y l psi

angle

L i k e most i n v e s t i g a t o r s who have used s e m i e m p i r i c a l methods t o s t u d y t h e c o n f o r m a t i o n s o f a s p a r t y l p e p t i d e s , we h a v e t r e a t e d t h e A s p r e s i d u e as a r e l a t i v e l y r i g i d z w i t t e r i o n . However, i t i s w o r t h w h i l e t o examine t h e f l e x i b i l i t y around t h e Asp C i ~ C bond ( t h e psi angle of t h e Asp r e s i d u e ) . F i g u r e 4 shows a p l o t o f energy v s . psi comput ed f o r Asp-Acc-OPr. The a s p a r t y l g r o u p psi a n g l e i s r e l a t i v e l y r e s t r i c t e d t o a r a n g e o f v a l u e s from about 8 0 - 1 8 0 ° , energetically b i a s e d toward the h i g h e r v a l u e s , which i s c o n s i s t e n t w i t h t h e f a c t t h a t i n t h e c r y s t a l s t r u c t u r e s o f b o t h aspartame and Asp-Acc-OPr t h e o b s e r v e d v a l u e i s about 150°. The minimum a t -80° i s not o n l y about 1.3 k c a l / m o l e h i g h e r , but i s a l s o i n a q u i t e n a r r o w p o t e n t i a l w e l l and i s o l a t e d by v e r y h i g h energy b a r r i e r s . Thus t h i s conformer would a


12.

TAYLOR E T AL.


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Figure 3. Phi-psi plot for the A c c residue i n A s p - A c c - O P r (crystal structure shown i n Figure 2 B ) . Energy above the global m i n i m u m is contoured i n 1 kcal/mole increments, up to 7 kcal/mole at the outer contour. The 4 preferred conformations are indicated by a - d . The crystal structure o f A s p - A c c - O P r corresponds to conformation b.

make o n l y a minor c o n t r i b u t i o n t o t h e o v e r a l l c o n f o r m e r p o p u l a t i o n a t room t e m p e r a t u r e . B a s e d on t h i s a n a l y s i s , t h e i n c o r p o r a t i o n by p r e v i o u s a u t h o r s (5-7) o f t h e X - r a y - l i k e c o n f o r m a t i o n o f t h e a s p a r tame Asp r e s i d u e i n t h e i r a c t i v e s i t e models a p p e a r s t o be r e a s o n a ble. T h i s r e s t r i c t i o n o f t h e Asp p s i a n g l e i s s i g n i f i c a n t , s i n c e t h e a s p a r t y l g r o u p f u n c t i o n s a s t h e e s s e n t i a l AH + Β m o i e t y i n s w e e t p e p t i d e a n a l o g s , and t h u s i t s o r i e n t a t i o n i s c r i t i c a l i n d e t e r m i n i n g the r e c e p t o r map. S i n c e t h e same Asp p s i a n g l e i s p r e f e r r e d i n b o t h aspartame and Asp-Acc-OPr, o v e r l a p p i n g t h e a s p a r t y l r e s i d u e o f p r e f e r r e d c o n f o r m a t i o n s o f t h e s e two m o l e c u l e s s h o u l d be t h e k e y t o d e t e r m i n i n g s i m i l a r i t i e s i n t h e i r mode o f b i n d i n g t o t h e sweet t a s t e receptor. The g l o b a l minimum energy s t a t e o f aspartame T h i s was c a l c u l a t e d by g r i d s e a r c h , u s i n g t h e s t a n d a r d T r i p o s f o r c e field. The a s p a r t a t e was t r e a t e d as r i g i d , e x c e p t f o r p s i , and t h e o t h e r d e g r e e s o f freedom were phi, psi, and X 2 o f Phe. This gave t h e c o n f o r m a t i o n shown i n F i g u r e 2D as t h e g l o b a l minimum. This conformation i s very c l o s e t o the X-ray c r y s t a l s t r u c t u r e , except



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TO ο UU

Molecular Mechanics of Cyclopropane Peptide Analogs of Aspartame

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